Txoj Kev Kynurenine-Kev Sib Txuas Tshiab Ntawm Innate Thiab Adaptive Immunity hauv Autoimmune Endocrinopathies Part 2

3.4. Kynurenines thiab Cheebtsam ntawm Innate Immune System

IFN- thiab lwm yam Th1 cytokines, xws li IL-1, TNF-, thiab IL-2, tuaj yeem txhawb kev ua haujlwm ntawm IDO1 [138]. Kev nthuav qhia ntawm lwm cov enzymes ntawm KP-KMO, KYNU, thiab 3-HAAO- kuj nyob rau hauv kev tswj ntawm IFN- [139]. Cov kws tshaj lij APCs, xws li DCs, monocytes, thiab macrophages, tuaj yeem nthuav qhia IDO1 tom qab IFN- raug [61,75], thiab lawv kuj tseem tuaj yeem nthuav tawm lwm cov enzymes ntawm KP hauv cov xwm txheej no. Tseeb tiag, nws tau pom tias tag nrho cov enzymes ntawm KP tau qhia hauv macrophages [140] thiab cov hlwb no tuaj yeem tsim qee cov kynureines, suav nrog AA, 3-HK, 3-HAA, PA, thiab QUIN, tom qab ua kom tiav [141].

Kev qhia ntawm QUIN tau pom nyob rau hauv peripheral monocytic hlwb ntawm cov neeg mob Alzheimer's disease [142]. Ntxiv mus, kab lis kev cai monocyte kho nrog IFN- thiab ntxiv nrog TRP tsim KYN thiab 3-HKYN, thiab neutrophils tsim KYN ib yam nkaus [63]. Ib yam li ntawd, kev qhia ntawm KP enzymes tau pom nyob rau hauv tib neeg monocyte-derived DCs, uas muaj peev xwm kho tau apoptosis ntawm Th cells tom qab stimulation nrog IFN- [143]. McIlroy et al. [144] pom tau tias DCs maturation ua rau tsim KYN, 3-HKYN, thiab 3-HAA. Noj ua ke, cov hlwb uas muaj kev tiv thaiv kab mob hauv lub cev, tshwj xeeb tshaj yog APCs, tuaj yeem ua rau TRP degradation thiab tsub zuj zuj ntawm kynurenines-TRP-derived metabolites nyob ib ncig ntawm lwm lub hlwb ntawm lub cev tiv thaiv kab mob.

Nws tau raug pom tias KYN metabolites, tshwj xeeb tshaj yog, KYN nws tus kheej, inhibit qhov kev ua ntawm NK hlwb thiab APCs. Loughman et al. [145] tau qhia tias KYN, 3-HKYN, thiab 3-HAA cuam tshuam cov tshuaj neutrophil chemotaxis thiab ncaj qha cuam tshuam lawv cov transepithelial migration induced los ntawm UPEC. Tsis tas li ntawd, TRP catabolism ntawm KP shave muaj qhov cuam tshuam tsis zoo rau cell viability. Kev sib sau ntawm TRP-derived metabolites yog tshuaj lom rau NK hlwb thiab monocyte-derived TPH-1 hlwb thiab tuaj yeem ua rau cov cell tuag los ntawm apoptosis [110,146]. Cov teebmeem no yog, tsawg kawg yog ib feem, kho los ntawm KYN ua kom AhR, uas tau nthuav tawm hauv txhua lub hlwb uas muaj nyob hauv lub cev tsis muaj zog.

Alzheimer's disease yog ib yam kab mob uas tshwm sim hauv cov neeg laus, uas tuaj yeem ua rau muaj qhov tshwm sim tsis zoo xws li kev nco thiab kev paub tsis meej. Nyob rau hauv xyoo tas los no, ntau thiab ntau cov kev tshawb fawb tau pom tias kev tiv thaiv kab mob ua lub luag haujlwm tseem ceeb hauv kev tshwm sim thiab kev loj hlob ntawm Alzheimer's disease.

Ua ntej, kev tiv thaiv kev tiv thaiv ncaj qha rau kev tshem tawm ntawm Alzheimer's kab mob-cov proteins uas cuam tshuam los ntawm lub hlwb. Nyob rau hauv ib txwm muaj xwm txheej, kev tu cov khib nyiab hauv lub hlwb feem ntau yog nyob ntawm qhov system glymphatic. Hauv Alzheimer's cov neeg mob, txawm li cas los xij, kev ua haujlwm ntawm lymphatic system feem ntau cuam tshuam, yog li lub cev tiv thaiv kab mob tau tso siab rau kom tshem tawm ntau tshaj amyloid.

Qhov thib ob, kev tiv thaiv kab mob tuaj yeem ua rau qeeb ntawm Alzheimer's kab mob los ntawm kev txo qis ntawm qhov mob. Inflammation yog ib qho ntawm cov laj thawj uas ntau cov kab mob neurological tau nce, thiab Alzheimer's kab mob tsis muaj kev zam. Cov kev tshawb fawb tau pom tias qee yam ntawm lub cev tiv thaiv kab mob tuaj yeem cuam tshuam qhov tshwm sim ntawm cov lus teb inflammatory, yog li txo cov tsos mob ntawm tus kab mob.

Tsis tas li ntawd, kev tiv thaiv kab mob kuj pab txhim kho kev nco thiab kev txawj ntse. Cov tshuaj tiv thaiv kab mob kuj tseem ua lub luag haujlwm tseem ceeb hauv kev sib txuas lus neuronal hauv lub hlwb. Ntau qhov kev tshawb fawb tau pom tias muaj qee lub cev tiv thaiv kab mob tuaj yeem pab txhawb kev sib cuam tshuam ntawm cov neurons, yog li txhim kho lub hlwb lub peev xwm kawm thiab nco.

Zuag qhia tag nrho, kev tiv thaiv kab mob ua lub luag haujlwm tseem ceeb hauv kev txhim kho Alzheimer's kab mob. Ntxiv nrog rau cov lus teb ntawm lub cev, cov kev xav ntawm lub hlwb kuj ua lub luag haujlwm zoo hauv kev tiv thaiv kev tiv thaiv. Txhawm rau tiv thaiv thiab kho tus kab mob Alzheimer, peb yuav tsum tswj hwm kev tiv thaiv kab mob zoo, thiab tswj tus cwj pwm zoo thiab kev cia siab rau hauv peb lub siab, muab kev txhawb nqa zoo rau peb lub cev thiab lub hlwb. Los ntawm qhov kev xav no, peb yuav tsum txhim kho kev tiv thaiv. Cistanche tuaj yeem txhim kho kev tiv thaiv kab mob, vim Cistanche yog nplua nuj nyob rau hauv ntau yam tshuaj antioxidant, xws li vitamin C, carotenoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem tshem tawm cov dawb radicals thiab txo oxidative kev nyuaj siab. Txhim kho qhov tsis kam ntawm lub cev tiv thaiv kab mob.

Nyem cistanche tubulosa cov txiaj ntsig

KYN tuaj yeem ua rau kev tsim tawm ntawm intracellular IDO1 los ntawm kev tawm tswv yim zoo, piv txwv li, KYN tuaj yeem koom nrog AhR hauv cytosol ntawm DCs, thiab KYN-AhR kev sib cuam tshuam tau ua rau muaj kev nthuav dav ntawm IDO1 qhia [87], nrog rau kev tawm tsam ib txhij ntawm stimulatory thiab co. -stimulatory molecules qhia hauv DCs, nrog rau txhawb kev tsim cov tshuaj tiv thaiv cytokines los ntawm cov hlwb no [147]. Ib yam li ntawd, KYNA kuj tau pom los qhib AhR, tab sis txawv ntawm KYN. Kev sib cuam tshuam ntawm KYNA/AhR ua rau tsim cov proinflammatory IL-6 [148]. Txawm li cas los xij, KYNA kuj yog ib qho ligand rau G protein-coupled receptor 35 (GPR35), uas yog qhia nyob rau hauv tib neeg monocytes, neutrophils, DCs, eosinophils, NK hlwb, thiab T hlwb. Kev sib cuam tshuam KYNA-GPR35 txo cov inflammatory teb nyob rau hauv monocytes thiab macrophages induced los ntawm stimulation nrog LPS thiab tswj cytokines tso tawm nyob rau hauv NK hlwb [149].

Hauv cov ntsiab lus, nws zoo nkaus li tias IDO1-kho KP ua kom muaj kev sib haum xeeb hauv cov hlwb ntawm lub cev tiv thaiv kab mob tuaj yeem ua rau muaj txiaj ntsig zoo rau kev txwv cov lus teb ntau dhau, tiv thaiv cov ntaub so ntswg hauv zos los ntawm kev puas tsuaj-kev puas tsuaj.

3.5. IDO1, KYN Pathway Metabolites, thiab Cov Cheebtsam ntawm Kev Tiv Thaiv Kev Tiv Thaiv 3.5.1. T Cells Subsets

T hlwb tau muab faib ua ob hom loj: cytotoxic T hlwb thiab T pab hlwb. T hlwb qhia txog CD4 molecule (CD4 ntxiv rau T hlwb) yog pab T (Th) hlwb, thaum T hlwb qhia CD8 molecule (CD8 ntxiv rau T hlwb) yog cytotoxic T hlwb, uas tuaj yeem ua rau cov kab mob malignant, kab mob, thiab senescent hlwb. 150] ib. Cov hlwb tseem ceeb heev rau kev tiv thaiv kab mob thaum lub sij hawm tus tswv tsev tiv thaiv cov kab mob phem, tab sis lawv tuaj yeem ua lub luag haujlwm tseem ceeb ua tus tsav tsheb ntawm cov kab mob autoimmune [151]. Tam sim no, Th cells tuaj yeem muab faib ua ntau pawg: Th1, Th2, Th17, Th22, Th9, follicular helper T cells (Tfh), thiab Tregs, nyob ntawm seb qhov profile ntawm cytokines lawv tsim [150,151]. Qhov sib txawv ntawm txhua qhov ntawm Th subset nyob ntawm qhov kev qhia ntawm cov kev hloov pauv tshwj xeeb: T-thawj koom ruam rau Th1 hlwb, GATA-binding protein 3 (GATA3) rau Th2 hlwb, retinoic acid receptor-related orphan receptor-t (ROR t) , AhR rau Th17 thiab Th22 hlwb, B cell lymphoma-6 (Bcl-6) rau Tfh hlwb, thiab Foxp3 rau Tregs [152]. Th cell subsets yog txhais los ntawm kos npe cytokines uas lawv nthuav qhia thiab lawv cov haujlwm tshwj xeeb effector.

Th1 hlwb raug txhais los ntawm lawv cov kev tsim tawm ntawm IL-2 thiab IFN-, tab sis kuj lawv tsim ntau cytokines, suav nrog TNF-, lymphotoxin, thiab GM-CSF. Th1 hlwb yog tshwj xeeb tshaj yog zoo ntawm activating macrophage microbicidal mechanisms tiv thaiv intracellular pathogens. Lawv koom nrog hauv cell-mediated o thiab ncua-hom hypersensitivity tshua [150,152].

Th2 hlwb yog qhov paub zoo tshaj plaws rau kev tsim cov IL-4, IL-5, thiab IL-13, nrog rau IL-9 thiab IL-10. Cov hlwb no ua lub luag haujlwm hauv kev tshem tawm cov kab mob extracellular thiab koom nrog kev ua xua thiab kab mob atopic [150,153]. Lawv feem ntau yog lub luag haujlwm rau kev tiv thaiv kev lom zem los ntawm kev ua kom B hlwb, mast hlwb, thiab tsim cov immunoglobulin E. Nws tau pom tias IL-4 qhia hauv vivo tuaj yeem tiv thaiv autoreactive B hlwb los ntawm apoptosis, txhim kho lawv txoj sia nyob, thiab induce activation ntawm autoreactive B hlwb [154]. Ntawm qhov tod tes, Th2 cytokines tuaj yeem kho kom haum rau kev tiv thaiv Th1-nyob ntawm qhov mob lossis tuaj yeem cuam tshuam ncaj qha Th1/Th17 kev loj hlob ntawm IL-4/IL-13, raws li [150].

Th17 hlwb yog lub hauv paus loj ntawm IL-17A (feem ntau hu ua IL-17) thiab IL-17F, txawm tias lwm cov hlwb, suav nrog NK hlwb thiab macrophages, kuj tau qhia qhia IB-17. IL-17 tsev neeg ntawm cytokines suav nrog ntau lub tebchaw koom nrog hauv kev tiv thaiv mucosal nto tiv thaiv cov kab mob extracellular. Tam sim no muaj rau tus neeg paub IL-17 tsev neeg, uas tau cim nrog cov ntawv ntawm A txog F [155]. IL-17A thiab IL-17F tau cuam tshuam rau hauv ntau qhov dav ntawm cov kab mob autoimmune-tom qab txuas nrog lawv cov receptors-IL-17RA thiab IL-17RC, ob qho tib si cytokines tuaj yeem ua rau muaj kev tso tawm ntawm cov cytokines pro-inflammatory, xws li IL-6, IL-1, IL-8, TNF- , thiab chemokine CXCL1, nyiam cov ntaub so ntswg mob, kev nrhiav cov neutrophils, ua kom muaj zog. ntawm lub cev tiv thaiv kab mob hauv lub cev thiab txhim kho B cell ua haujlwm [156]. Tsis tas li ntawd, IL-17 signaling induces tso tawm ntawm lwm inflammatory mediators, xws li intercellular adhesion molecule 1 (ICAM-1), prostaglandin E2, thiab matrix metalloproteinases, uas tej zaum yuav pib ob peb zoo-feedback loops uas ntxiv mus. IL-17 tso zis, ua rau mob o thiab cov ntaub so ntswg puas [157]. Dhau li ntawm IL-17, Th17 hlwb tseem tuaj yeem tso tawm IL-21, IL-22, IL-25, thiab IL-26 (hauv tib neeg); Txawm li cas los xij, feem ntau ntawm cov kab mob ua haujlwm ntawm Th17 hlwb tau cuam tshuam nrog kev tso tawm ntawm IL-17 [158]. Vim yog lub luag haujlwm tseem ceeb ntawm IL-17A thiab IL-17F hauv kev ua kom cov nqaij ntshiv, Th17 hlwb tau pom tias ua lub luag haujlwm tseem ceeb hauv etiopathogenesis ntawm ntau yam kab mob autoimmune, uas Th1 yog thawj zaug txiav txim siab. ib qho tseem ceeb. Th17 muaj nuj nqi nyob ntawm kev sib txuas ntawm cytokines qhia nyob rau hauv ib puag ncig hauv zos, thiab kev tswj hwm ntawm cov hlwb kev sib txawv yog kho los ntawm ib qho nyuaj cytokine thiab transcription factor, uas yuav ua rau ob qho tib si pathologic thiab tiv thaiv kev ua haujlwm ntawm cov hlwb hauv inflammatory thiab autoimmune kab mob.

Nws tau raug pom tias Th17 hlwb tuaj yeem tsim cov tshuaj tiv thaiv kab mob cytokine IL-10 thaum lawv tau txhawb nqa nrog IFN- lossis IFN- [159]. Ntawm qhov tsis sib xws, IL-23 tau pom tias txo qis kev qhia ntawm IL-10 hauv kev tsim cov Th17 hlwb, ua rau muaj kev cuam tshuam ntawm Th17 subset uas tuaj yeem tsim IL-17 [160]. Tsis tas li ntawd, Th17 hlwb nthuav tawm cov yas siab-lawv tuaj yeem sib txawv rau lwm T cell subsets hauv ntau qhov chaw, piv txwv li, Th17 hlwb tuaj yeem hloov los ntawm IL-6 mus rau Th1 hlwb tsim IFN- [161].

Tregs ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob thiab kev tswj hwm ntawm autoimmunity [162]. Tregs qhia txog qhov kos npe ntawm kev sau npe-Foxp3-uas yog qhov tseem ceeb hauv lawv txoj kev loj hlob, kev sib txawv, thiab kev tswj hwm kev ua haujlwm [163]. Foxp3 qhia Treg subsets suav nrog ob qho tib si tshwm sim Tregs (nTregs) tsim nyob rau hauv thymus thiab induced ntawm post-thymic maturation Tregs (iTregs), uas tuaj yeem sib txawv ntxiv rau hauv Foxp3 ntxiv hlwb (Th3) thiab Foxp3- hlwb, hu ua Tr1 [164]. . Th3 sib txawv tshwm sim feem ntau tom qab qhov ncauj noj ntawm exogenous antigens, thiab cov hlwb no pab lub secretion ntawm IgA los ntawm tso TGF- thiab qhia suppressive zog txog Th1 thiab Th2 hlwb [165]. Tr1 hlwb, ua qhov tseem ceeb ntawm IL-10 hauv lub cev tiv thaiv kab mob, ua lub luag haujlwm tseem ceeb hauv kev cuam tshuam ntawm autoimmunity thiab o [166]. Cov tshuaj tiv thaiv kab mob ntawm IL-10 tau kho los ntawm nws qhov cuam tshuam rau kev txo qis ntawm kev qhia ntawm MHC-II thiab co-stimulatory molecules: CD80, CD86, thiab CD28 ntawm APCs, thiab kev txo qis ntawm kev ua haujlwm. mast hlwb, macrophages thiab txo qhov tso tawm ntawm lawv cov proinflammatory cytokines [167].

TGF- yog tsim los ntawm nTreg thiab Th3 hlwb; Txawm li cas los xij, ntau lub cev tiv thaiv kab mob thiab tsis muaj kab mob kuj tseem tuaj yeem tsim cov cytokine no. TGF- xav tau rau tiam iTregs vim qhov induction ntawm Foxp3 qhia tsav los ntawm TGF- converts naive T hlwb rau hauv Tregs. Qhov kev tawm tswv yim zoo no ntawm TGF- thiab Foxp3 ua lub luag haujlwm tseem ceeb hauv kev tswj xyuas qhov kev ua siab ntev thiab kev saib xyuas ntawm Tregs [168]. Nyob rau hauv vivo, TGF- tsim Tregs tau pom tias yuav txwv tsis pub autoimmune T cell teb, inhibit IL{10}} ntau lawm, thiab txhim khu kev qhia ntawm Foxp3 hauv Th cells [169].

Niaj hnub no, Tregs tau lees paub tias yog ib qho tseem ceeb ntawm cov tshuaj tiv thaiv kab mob hauv ntau cov kab mob inflammatory thiab autoimmune, thiab cov kev kho mob ntawm tes siv cov hlwb tam sim no tab tom nrhiav kev kho mob rau kev kho cov kab mob no [170,171]. Txawm li cas los xij, nws tsim nyog nco ntsoov tias qee qhov cytokines tsim los ntawm Tregs, suav nrog IL-10 thiab TGF- , tej zaum yuav tsis muaj peev xwm tiv thaiv kab mob, thiab nyob rau qee qhov xwm txheej, lawv tuaj yeem txhim kho kev ua haujlwm thiab kev ua haujlwm ntawm cov kab mob pathogenic. . Nws tau raug pom tias IL-10 tuaj yeem qhib cov hlwb B, ua kom lawv txoj haujlwm ua APCs thiab tsav kev loj hlob ntawm B hlwb rau hauv cov ntshav plasma [172]. TGF- kuj tseem cuam tshuam nrog ntau yam kev mob tshwm sim, zoo li kev txhim kho ntawm IL-17- tsim Th17 hlwb, uas txhawb kev mob [158]. TGF- tuaj yeem tsim IL-9- tsim cov Th cells, uas txhawb cov ntaub so ntswg pathology. Ob leeg TGF- thiab IL-10 txhim kho txoj sia nyob ntawm CD8 ntxiv rau T hlwb thiab nce lawv cov khoom tsim tawm ntawm IL-17 thiab IFN- [173,174]. Qhov tshwm sim no zoo li tej zaum yuav yog ib txoj hauv kev uas lub cev tiv thaiv kab mob tswj nws qhov sib npaug.

3.5.2. IDO1, Kynurenines, thiab T Cells

Raws li tau hais los saum toj no, IDO1 induction nyob rau hauv cov hlwb uas muaj nyob rau hauv lub cev tiv thaiv kab mob coj mus rau lub depletion ntawm TRP thiab tiam ntawm KYN thiab nws cov metabolites (Daim duab 2), uas yog cov tseem ceeb regulators ntawm adaptive immunity [25], pab mus rau lub sij hawm ntev. - Kev tiv thaiv kab mob ntev ntev los ntawm ntau lub tshuab sib txawv (Daim duab 3).

Ib qho ntawm cov kev xav ua ntej tshaj tawm tias TRP kev puas tsuaj cuam tshuam T cell proliferation los ntawm kev txo cov peev txheej ntawm cov amino acid no hauv cov ntaub so ntswg hauv zos microenvironments. Nws tau raug postulated tias TRP-tsis muaj T hlwb tsis tuaj yeem tsim cov proteins txaus rau kev loj hlob tom qab kev nthuav qhia antigen los ntawm APCs [175]. IDO1-dependent TRP depletion ua rau cov amino acid sensor-GCN2K hauv CD4 ntxiv rau T hlwb [176]-uas tswj cov kev hloov pauv thiab kev txhais lus sib txuas ntawm tes kev loj hlob rau cov amino acid muaj [177]. Los ntawm kev ua kom GCN2K, IDO1 tuaj yeem txo qis cov enzymes koom nrog fatty acid synthesis hauv CD4 ntxiv rau T hlwb [176]. Fatty acid synthesis yog tswj raws li T cell activation thiab yog tsim nyog los tiv thaiv kev tuag ntawm proliferating hlwb [178].

Yog li, IDO1- nyob ntawm kev ua kom GCN2K thiab txo cov fatty acid synthesis impairs CD4 ntxiv rau T cell proliferation thiab sib txawv rau hauv effector cell lineages. Fallarino et al. [81] ua pov thawj tias ob qho tib si TRP depletion thiab sib xyaw ntawm TRP metabolites loj: KYN, 3-HKYN, thiab 3-HAA tuaj yeem ua rau GCN2K- nyob ntawm kev tswj hwm ntawm T cell receptor (TCR) complex zeta -chain hauv CD8 ntxiv rau T hlwb, uas ua rau muaj kev cuam tshuam cytotoxic effector kev ua haujlwm ntawm cov hlwb. Thaum CD4 ntxiv rau CD25- T hlwb hauv cov xwm txheej no tau hloov mus rau Treg phenotype los ntawm txoj kev xav tau GCN2K, txo qis hauv IL-2 ntau lawm, thiab nce IL-10 thiab TGF- . TRP tshaib plab ntawm IDO1 tsis tsuas yog ua los ntawm TCR inactivation, tab sis, nrog rau induction ntawm Fas, mediates cell voj voog ntes nyob rau hauv nruab nrab-G1 theem ua rau T cell apoptosis, clonal anergy, thiab inhibition ntawm antigen-specific T cell teb [ 56] ib.

Kev tshawb fawb tshiab ntawm Eleftheriadis et al. [179] pom tias IDO1, los ntawm kev ua kom GCN2K, txo qis cov theem ntawm TCR complex zeta saw thiab cMyc, uas ua rau txo qis ntawm cov enzymes tseem ceeb koom nrog hauv aerobic glycolysis thiab glutaminolysis, uas yuav tsum tau rau kev loj hlob sai, qhib T hlwb. Cov kev tshawb fawb qhia tau siv KKYN-dawb APCs-dawb system ntawm kev sib cais thiab qhib T cells, thiab cov kws sau ntawv tau pom tias qhov kev ua kom ncaj qha ntawm GCN2K los ntawm TRP yog txaus rau inhibition ntawm T cell proliferation thiab qhov no tej zaum yuav yog ib tug intrinsic cell mechanism rau. tswj kev loj hlob. Ntxiv mus, 3-HAA tau pom tias ua rau muaj kev tiv thaiv kab mob los ntawm kev ua kom apoptosis hauv T hlwb los ntawm glutathione depletion [80]. Hayashi et al. [180] tau txheeb xyuas lwm txoj hauv kev muaj peev xwm ntawm 3-HAA kev ua, cuam tshuam nrog inhibition ntawm 3-phosphoinositide-dependent protein kinase signaling hauv T hlwb, uas ua rau T cell apoptosis.

Hauv feem ntau ntawm kev xa mus rau cov kev tshawb fawb, cov tshuaj tiv thaiv kab mob ntawm IDO1 tau raug soj ntsuam hauv kab lis kev cai xov xwm tsis muaj roj fatty acids. Txawm li cas los xij, thaum cov roj fatty acids dawb tau ntxiv rau cov kab lis kev cai ntawm tes, IDO1 tau nce cov roj fatty acid oxidation thiab txawm tias nws txhawb Tregs sib txawv, nws tsis ua rau apoptosis lossis inhibited qhov kev loj hlob ntawm CD4 ntxiv rau T hlwb [181]. Txawm hais tias IDO1 txo qis glycolysis thiab glutaminolysis los ntawm kev ua kom GCN2K, nws tuaj yeem ua rau cov roj ntsha dawb oxidation los ntawm kev ua kom AhR, muab lub zog tsim nyog rau CD4 ntxiv rau T cell ciaj sia taus thiab kev loj hlob [182]. Yog li, tsis sib xws rau yav dhau los kev xav tias IDO1- txoj kev kho kom haum xeeb tau txwv CD4 ntxiv rau T cell ua haujlwm los ntawm kev ua kom apoptosis, inhibiting proliferation, thiab txhawb kev sib txawv ntawm kev tswj hwm T cell phenotype, cov ntaub ntawv tsis ntev los no tau qhia tias nyob rau hauv ib puag ncig ib puag ncig. muaj cov fatty acids, immunosuppressive nyhuv ntawm IDO1 tsis tuaj yeem raug ntaus nqi rau qhov txo qis hauv CD4 ntxiv rau T cell proliferation thiab ciaj sia taus.

IDO1, Kynurenines, thiab Th1/Th2 Cells sib npaug

Cov ntaub ntawv sim tau pom tias IDO1 muaj cov cuab yeej tiv thaiv kab mob tseem ceeb cuam tshuam nrog kev tiv thaiv kab mob thiab kev tswj hwm Th1 / Th2. Kev nthuav qhia ntawm IDO1 hauv DCs ua rau muaj kev cuam tshuam ntawm tib neeg T-cell proliferation, tsim kom muaj kev tiv thaiv kab mob hauv zos [75]. IDO1 kev ua haujlwm hauv pDCs thaiv kev nthuav dav ntawm CD4 ntxiv thiab CD8 ntxiv rau T hlwb, thiab tsim cov cytotoxic T lymphocytes (CTLs) thiab Th1 hlwb, thaum muaj kev cuam tshuam tsawg rau Th2 hlwb [80]. Ib txoj hauv kev zoo sib xws tau pom txog IDO1- qhia txog tib neeg eosinophils, uas nyiam inhibit Th1 hlwb tab sis txhawb Th2 hlwb [62]. Ntxiv mus, qhov txo qis hauv Th1 cytokine ntau lawm thiab nce hauv Th2 cytokine theem tau pom nyob rau hauv murine spleen hlwb tom qab pharmacological inhibition ntawm IDO1 [183]. Cov txiaj ntsig no tau qhia tias qhov kev nyiam tshaj plaws ntawm apoptosis hauv Th1 hlwb, tab sis tsis yog hauv Th2 hlwb, yog vim muaj kev cuam tshuam ntau dua ntawm Th1 hlwb rau IDO1-induced KYN ntau lawm lossis tsim cov metabolites downstream ntawm KP [184].

Txawm li cas los xij, hauv vivo, kev tshawb fawb ntawm ovalbumin-induced hawb pob hauv nas tau muab cov txiaj ntsig tsis sib xws. IDO1- cov tsiaj tsis muaj peev xwm pom tau tias tsis muaj zog Th2 cov lus teb hauv kev sib piv rau kev tswj hwm, thaum cov neeg sib tw nrog cov tshuaj nqus tau antigen thiab lawv cov qib ntawm cov tshuaj tiv thaiv tshwj xeeb IgE qis dua, qhia tias IDO1- tsis txaus tiv thaiv ovalbumin-induced hawb pob [ 185] ib. Thaum, hauv lwm tus qauv murine ntawm kev mob ntsws asthma siv tib qhov kev xav, induction ntawm IDO1 qhia inhibited Th2-induced hawb pob [186]. Cov lus piav qhia dav dav rau cov kev tsis sib haum xeeb no tau ua los ntawm MacKenzie li al. [187], leej twg pom tias thaum lub sij hawm antigens thiab pathogens nthuav qhia los ntawm DCs rau T hlwb, naive Th hlwb hloov mus rau Th1 subsets, thiab INF- ntau lawm tsim ib tug Th1 dominant microenvironment, inhibiting Th2 txawv. Raws li IFN- induces DCs los nthuav qhia IDO1, txo qis hauv TRP theem, cuam tshuam nrog kev nce hauv kynurenines, ua rau Th1 hlwb apoptosis thiab xaiv ciaj sia taus ntawm Th2 hlwb, ua raws li kev cai voj kom txwv tsis pub dhau Th1 hlwb teb.

Cov pov thawj tsis ntev los no qhia tau hais tias cov cuab yeej immunomodulatory ntawm IDO1 feem ntau yog los ntawm kev sib sau ntawm KYN metabolites ua ke nrog TRP depletion [32]. Nws tau raug pom tias KP catabolite yog cov tseem ceeb hauv kev sib kho hauv kev tswj hwm Th1 thiab Th2 cell muaj nuj nqi, txawm tias Th2 hlwb tsis tshua nkag siab rau TRP metabolites [188]. Qhov sib ntxiv ntawm exogenous KYN metabolites KYN, 3-HAA, QA, 3-HKYN, thiab PA rau T hlwb kab lis kev cai qhia tau hais tias cov tebchaw yuav inhibit proliferation thiab induce apoptosis ntawm active T hlwb ntawm ntau physiologically cuam tshuam TRP ntau ntau dua. yav dhau los "TRP depletion" txoj kev xav yuav qhia [59,110,183,189]. HAA thiab QUIN induced xaiv apoptosis hauv vitro ntawm murine Th1 tab sis tsis Th2 hlwb. Cov txheej txheem no tau pom nyob rau ntawm qhov tsis tshua muaj siab ntawm cov kynurenines, tsis xav tau Fas / Fas ligand kev sib cuam tshuam, thiab cuam tshuam nrog kev ua kom cov caspase-8 thiab tso tawm cytochrome c los ntawm mitochondria [80]. Orihara et al. [190] pom tau tias QUIN muaj peev xwm txo tau Th1 cytokines ntau lawm, Ca2 ntxiv flux, proliferation, thiab ciaj sia taus ntawm Th1-zoo li hlwb los ntawm kev nce induction ntawm cell tuag, whereas Th2-zoo li cov hlwb tau dim, ua rau nce Th2-zoo li dominance. Kev sib koom ua ke, kev hloov pauv ntawm Th1 / Th2 tshuav nyiaj li cas nyiam Th2 hlwb kev muaj sia nyob evoked los ntawm KP ua kom zoo li txwv tsis pub muaj kev tswj hwm ntawm kev tiv thaiv kab mob.

Nws yuav tsum tau hais tias piav qhia txog cov teebmeem ntawm KP metabolites ntawm kev ua haujlwm thiab kev muaj peev xwm ntawm cov hlwb ntawm lub cev tiv thaiv kab mob tuaj yeem raug kho los ntawm AhR, uas yog misexpressed hauv qee yam subtypes ntawm T hlwb, xws li naive Th, Th17, thiab Treg hlwb, qhov sib txawv tag nrho Th1 hlwb tsis tuaj yeem tswj hwm AhR tom qab ua haujlwm thiab tsis tuaj yeem hloov kho ncaj qha los ntawm AhR ligation [191]. Lub tshuab ua haujlwm AhR suppresses lub cev tiv thaiv kab mob hauv cov xwm txheej ib txwm muaj, qhov kev txo qis ntawm AhR kev ua haujlwm txhim kho cov lus teb no [192]. Txawm li cas los xij, cov txiaj ntsig ntawm kev tshawb fawb tshawb xyuas lub luag haujlwm ntawm AhR hauv kev hloov kho lub cev tiv thaiv kab mob qee zaum sib txawv. Kev ua kom lub AhR los ntawm ib puag ncig cov co toxins txawv ntawm qhov pom tom qab kev txhawb nqa nrog nws cov ligands ntuj, piv txwv li, AhR ua kom T hlwb los ntawm dioxin tau pom tias inhibit kev tiv thaiv los ntawm tiam Tregs, thaum nws ua rau kev tiv thaiv tsis zoo tom qab ua kom muaj zog los ntawm {{5} }formylindolo [3,2-b]carbazole (FICZ), ib qho endogenous ligand muab los ntawm TRP [193].

Hauv kev pom zoo nrog qhov kev xav no, Ambrosio li al. [194] pom tias kev kho dioxin ntawm Trypanosoma cruzi kab mob hauv cov nas ua rau muaj kev tuag ntau ntxiv ntawm cov kab mob T hlwb thiab nce tus naj npawb ntawm Tregs ua TGF- . Qhov tsis muaj zog AhR ligand-3-HKYN- kuj tseem tuaj yeem ua rau Tregs thiab txhim kho qhov tsis sib haum xeeb ntawm cov kab mob T hlwb thiab Tregs thaum lub sij hawm tus kab mob, tab sis nws tsuas yog ib feem ntawm kev tswj cov kab mob parasitemia thiab tsis muaj peev xwm. kom tshem tawm nws. Ntxiv mus, qhov cuam tshuam tsis zoo ntawm kev ua kom muaj zog AhR ntawm kev txhim kho kev nco CD8 ntxiv rau T hlwb kuj tau pom. AhR ligation txwv qhov sib txawv ntawm CD8 ntxiv rau lub cim xeeb T hlwb, tej zaum los ntawm kev tsis ncaj, AhR-raws li kev tswj hwm ntawm DCs, zoo ib yam li qhov no pom nrog Th1 hlwb [193].

IDO1, Kynurenines thiab Tregs/Th17 Cells Balance

IDO1 pab txhawb kev tiv thaiv kab mob los ntawm kev pab Tregs effector muaj nuj nqi. Hauv murine pDCs kho nrog TGF- , IDO1 tuaj yeem tsim cov cim qhia txog kev tiv thaiv kab mob ntev ntev los ntawm kev hloov CD4 ntxiv rau T hlwb rau hauv cov tshuaj tiv thaiv kab mob Foxp3 ntxiv rau Tregs [81,195], uas, dhau los, tuaj yeem ua rau IDO1 qhia hauv pDCs thiab neutrophils [83]. Kev ua haujlwm tsis muaj zog Tregs tau txais cov haujlwm muaj zog tiv thaiv thaum cocultured nrog IDO{10}} qhia pDCs. Nws yog ib qho tsim nyog sau cia tias IDO1-pDCs muaj peev xwm tiv thaiv qhov cuam tshuam T hlwb teb thiab txhawb kev sib txawv ntawm Tregs tsuas yog thaum cov xwm txheej hauv zos lossis kev kho mob induce pDCs los nthuav qhia IDO1 thiab GCN2K signaling kuj tseem ceeb rau Tregs activation. Ntxiv mus, qhov no IDO1 / GCN2K-dependent txheej txheem ntawm Tregs ua kom raug MHC-txheej txheem thiab tau tiv thaiv los ntawm CTLA4 blockade [196]. B7 receptors ntawm IDO1- zoo DCs khi rau CTLA4 ntawm Tregs ua rau lawv loj hlob, thiab kev thaiv ntawm CTLA4 / B7 axis ua rau IDO1 enzymatic kev ua si thiab Tregs ua kom, qhia tias CTLA4 ntxiv rau Tregs ligate B7 ntawm pDCs los tswj IDO1 kev ua haujlwm hauv pDCs [84]. Tregs tau qhib los ntawm IDO1 zoo kawg li txhawb nqa PD-L1 thiab PD-L2 kev qhia ntawm lub hom phiaj DCs, thiab lub peev xwm ntawm Tregs los tiv thaiv T cell proliferation raug tshem tawm los ntawm cov tshuaj tiv thaiv tawm tsam PD-1 / PD-L txoj hauv kev tab sis tsis nyob ntawm IL-2, IL-10, or TGF- [196].

Yog li ntawd, IDO1 kev ua hauv pDCs txhawb nqa de novo Treg sib txawv los ntawm naive CD4 ntxiv rau cov neeg ua ntej, thiab cov txiaj ntsig zoo ib yam tshwm sim thaum tsis muaj CD4 ntxiv rau cov neeg ua ntej tau coj los ua ke nrog qis TRP / siab kynurenines nruab nrab, ncaj qha cuam tshuam TRP catabolism hauv Tregs tiam [81]. Ntxiv mus, IDO1 qhia tau pom los thaiv kev hloov pauv ntawm Tregs rau Th17 hlwb los ntawm kev ua haujlwm ntawm GCN2K txoj hauv kev thiab kev tawm tsam ntawm IL-6 ntau lawm hauv pDCs [82]. Hauv qhov no, IDO1 tsis tsuas yog cuam tshuam cov nyhuv T hlwb ncaj qha tab sis kuj tsis ncaj qha tuaj yeem cuam tshuam Tregs suppressor kev ua haujlwm txog Th1, Th2, lossis Th17 hlwb. Txawm li cas los xij, qhov inhibition ntawm T cell teb / kev loj hlob zoo li yog nyob ntawm microenvironment, txij li thaum qhov tshwm sim ntawm Tregs rau proinflammatory IL -6 tau lees paub los hloov cov Tregs paub tab rau hauv phenotype recalling Th17 hlwb [197]. Nyob rau hauv lem, KYN tshwm sim los ntawm kev ua kom IDO1 txhawb ib tug se IDO1 qhia los ntawm ib tug agonistic ua ntawm AhR nyob rau hauv DCs [77,78,198], tsim ib tug zoo loop txhawb IDO-mediated teebmeem nyob rau hauv cov hlwb. Ligand activation ntawm AhR ob leeg ntawm T hlwb thiab pDCs tau tshaj tawm los pab txhawb rau Tregs txoj kev loj hlob thiab Th17 tsub kom [199,200]; Txawm li cas los xij, nws kuj tau pom tias yuav qhib IDO1 hauv DCs [198], qhia txog lub voj voog tom ntej hauv KYN-induced AhR activation. Nyob rau hauv txoj kab nrog cov no, lub luag haujlwm tiv thaiv ntawm IDO1 ua rau hauv kev sim autoimmune encephalomyelitis (EAE) hauv nas tau pom [201], thiab IDO1 qhia hauv DCs raug ntxias los ntawm kev tswj hwm tshuaj estrogen coj mus rau concomitant T cell apoptosis txuam nrog EAE suppression thiab txo tus nqi. rov qab thaum cev xeeb tub [202] Nyob rau hauv sib piv, cov pharmacological blockage ntawm IDO1 ua rau muaj zog Th1 thiab Th17 cov lus teb, txo Treg cov lus teb, thiab EAE exacerbation tag nrho [203].

KYNA kuj tau raug txheeb xyuas tias yog tus muaj zog agonist ntawm AhR [148], txawm li cas los xij, cov kev tshawb fawb ncaj qha qhia qhov ua tau ntawm AhR-mediated nyhuv ntawm KYNA ntawm kev hloov kho ntawm Treg / Th17 axis tsis muaj. Thaum, KYNA tau raug tshaj tawm kom txo IL-17 kev qhia hauv lub hlwb T hlwb thiab ua kom cov Th17 hlwb ua rau lwm txoj hauv kev - los ntawm kev ua ntawm G-protein-coupled receptor 25 (GPR35) ntawm DCs, ua rau muaj kev tawm tsam ntawm lawv cov IL. -23 ntau lawm [204]. Txawm li cas los xij, kev tshawb fawb tsis ntev los no ntawm Engin et al. [205] pom tias qhov sib txuam ntawm KYNA, vim yog overexpression ntawm IDO1 los ntawm AhR activation, induces AhR/IL-6/STAT3 signaling pathway thiab sib txawv ntawm naive CD4 ntxiv rau T hlwb mus rau Th17 hlwb. Whereas nws inhibits Tregs, ua rau Treg/Th17 imbalance thiab cytokine cua daj cua dub, uas ua rau lub txim tuag ntawm SARS-CoV-2 kab mob. Qhov kev tshawb pom tshiab no qhia tias KYNA tuaj yeem ua lub luag haujlwm sib txawv rau KYN hauv kev hloov pauv qhov sib npaug ntawm Treg / Th17 axis. Qhov no yog ua raws li qhov kev soj ntsuam yav dhau los uas IDO1 ua lub luag haujlwm tseem ceeb hauv kev hloov pauv ntawm Tregs rau hauv Th17 hlwb los ntawm kev thaiv IL-6 ntau lawm, uas yog xav tau rau qhov kev hloov pauv no. Lub phenotype ntawm reprogrammed Tregs tom qab IDO1- thaiv tau piav raws li zoo li "multifunctional T-helper cells", co-expressing txawv cytokines, xws li IL-2, IL-17, IL{{ 29}}, thiab TNF- [206].

Lwm qhov dej ntws ntawm KYN metabolite-3-HAA- tau pom tias txo qis Th1 thiab Th17 cov lus teb thiab txhawb nqa Treg cov lus teb, ib feem los ntawm kev ua tsis ncaj ntawm DCs. Kev tswj hwm ntawm qhov sib xyaw no ua rau muaj kev hloov pauv ntawm EAE hauv cov nas [203]. DCs kho nrog 3-HAA hauv vitro txo ​​lawv cov IL-6 ntau lawm thiab nthuav qhia TGF- . Ntxiv mus, thaum 3-HAA-kho DCs tau cocultured nrog naive CD4 ntxiv rau T hlwb, tiam ntawm Tregs tau txhawb nqa [203]. Cov txiaj ntsig no tau pom tias IDO1, los ntawm tiam ntawm 3-HAA, tuaj yeem txhim kho TGF- kev qhia hauv DCs thiab txhawb kev sib txawv ntawm Tregs. Ntxiv mus, txoj kev kho nrog N-(3,4,-dimethoxy cinnamoyl) anthranilic acid, ib qho kev ua haujlwm ntawm qhov ncauj ntawm 3-HAA analog (tranilast), zoo li tau pom muaj kev cuam tshuam hauv EAE, nrog tsawg dua thiab mob hnyav dua pom hauv cov tsiaj kho [207].

Ib yam li ntawd, cinnabarinic acid, uas tsis tshua paub txog endogenous KYN metabolite, muaj peev xwm tiv thaiv EAE los ntawm kev txhim kho Tregs ntawm tus nqi ntawm Th17 [208].

Hauv cov ntsiab lus, KYN thiab nws cov metabolites downstream cuam tshuam qhov sib npaug ntawm Th17 / Tregs system, hloov qhov nyiaj tshuav no los ntawm kev tiv thaiv Tregs.

3.6. Kynurenines thiab IL-2 Kev Qhia

Lub cim xeeb CD4 ntxiv rau T hlwb yog ib qho tseem ceeb los xyuas kom meej lub cev tiv thaiv kab mob ntev, thiab lawv cov depletion yog txuam nrog mob tsis tu ncua. Kev ciaj sia ntawm lub cim xeeb CD4 ntxiv rau T hlwb nyob ntawm cov teeb liab muab los ntawm -chain-receptor cytokines, xws li IL-2 [209]. Dagenais-Lussier thiab cov neeg ua haujlwm ua haujlwm [210] tau pom tias qhov kev tsim tawm ntawm KYN muaj feem cuam tshuam nrog qhov tsis zoo IL-2 teeb liab hauv nco CD4 ntxiv rau T hlwb los ntawm cov kab mob HIV, ua rau lawv cov Fas-mediated apoptosis. Kev kho mob ntawm kev nco CD4 ntxiv rau T hlwb nrog lub cev muaj zog ntawm KYN (5 µM) hauv vitro inhibited IL{15}} qhia los ntawm cov txheej txheem ntsig txog kev tsim khoom ntawm ROS [210].

Ua ke, nthuav tawm hauv cov ntaub ntawv no qhia tias IDO1 ua kom muaj peev xwm hloov pauv txoj haujlwm ntawm APCs thiab hloov cov T hlwb hauv zos 'kev ua haujlwm los ntawm ib qho tshuaj tiv thaiv kab mob mus rau ib qho tolerogenic. Txawm li cas los xij, KP enzymes downstream ntawm IDO1 tuaj yeem pib tolerogenesis los ntawm DCs ntawm nws tus kheej ntawm TRP deprivation. Kev tsim cov tshuaj paracrine ntawm kynurenines tej zaum yuav yog ib lub tswv yim siv los ntawm IDO1-cov hlwb muaj peev xwm los hloov DCs uas tsis muaj cov enzyme no ua rau tolerogenic phenotype hauv IFN- - ib puag ncig nplua nuj [211]. Ntawm qhov tod tes, qee qhov kev tshawb fawb tau txheeb xyuas IDO1- tshwj xeeb CD4 ntxiv thiab CD8 ntxiv rau T hlwb hauv cov neeg noj qab haus huv thiab cov neeg mob qog noj ntshav uas muaj peev xwm tshem tawm IDO1- qhia cov hlwb, suav nrog IDO1- zoo DCs thiab qog hlwb. Qhov kev tiv thaiv tiv thaiv-IDO1 no tej zaum sawv cev rau kev tiv thaiv kev tswj hwm, txhawm rau txwv IDO1-kev tiv thaiv kab mob sib kis los txhawb cov tshuaj tiv thaiv kab mob tshwj xeeb [212–214].

3.7. IDO1 thiab B Cells

Txawm hais tias feem ntau ntawm cov ntaub ntawv tau tsom mus rau kev tshawb nrhiav qhov cuam tshuam ntawm IDO1 ntsig txog T hlwb, ntau qhov kev tshawb fawb tau soj ntsuam lub luag haujlwm ntawm IDO1 hauv B hlwb cov lus teb. Lub luag haujlwm tseem ceeb ntawm B hlwb yog tsim cov tshuaj tiv thaiv. Txawm li cas los xij, ib qho subpopulation ntawm B hlwb uas tswj lub cev tiv thaiv kab mob ntawm nws tus kheej ntawm cov tshuaj tiv thaiv kab mob tau raug txheeb xyuas [215]. Cov hlwb no, hu ua kev tswj hwm B lymphocytes (Bregs) tau tshawb pom raws li lawv lub peev xwm los cuam tshuam cov txheej txheem tiv thaiv kab mob [216] los ntawm IL-10-raws li cov txheej txheem, uas yog lub luag haujlwm rau kev tswj xyuas qhov mob [217]. Tshaj li ntawm IL -10 ntau lawm, muaj qee cov lus qhia tias ib feem ntawm qhov kev tiv thaiv kab mob no ntawm Bregs yog nyob ntawm kev cuam tshuam nrog lwm cov kab ke tswj hwm ntawm tes; lawv tuaj yeem cuam tshuam Th1 thiab Th17 qhov sib txawv thiab ua rau muaj kev cuam tshuam ncaj qha ntawm kev nthuav qhia antigen los ntawm DCs, thaum lawv induce Tregs txawv [218].

Xyoo 2009, Scott et al. [219] pom tias pharmacological inhibition ntawm IDO1 kev ua ub no tau npaj txhij txog qhov tshwm sim ntawm ameliorating mob caj dab hauv cov qauv rheumatoid mob caj dab hauv nas. Qhov txo qis ntawm cov tsos mob ntawm kev mob caj dab no tau tshwm sim los ntawm qhov txo qis autoreactive B cell teb, xav txog qhov txo qis autoantibody titers, qhov tsis muaj qhov sib txawv ntawm qhov feem pua ​​​​ntawm Tregs, lossis qib ntawm Th1 / Th2 / Th17 cytokines. Hauv qhov sib piv, cytokines cuam tshuam nrog kev mob, xws li MCP-1, IL-6, thiab IL-10, tau txo qis hauv cov nas no. Txoj kev tshawb no pom tau hais tias IDO1 ua lub luag haujlwm tseem ceeb hauv kev tsim cov autoreactive B cell profile thaum pib ntawm cov lus teb autoimmune, qhia nws lub luag haujlwm yav dhau los tsis txaus siab rau kev txhawb nqa ntawm B cell ua haujlwm. Qhov kev tshawb pom no tau pom tias IDO1 tsis yog tsuas yog tiv thaiv kab mob xwb tab sis kuj ua lub luag haujlwm nyuaj dua hauv kev hloov kho cov lus teb, tshwj xeeb yog tsav los ntawm autoreactive B hlwb.

Ib xyoos tom qab, Vinay li al. [220] tau qhia txog qhov muaj nyob ntawm murine B lymphocyte subpopulation, uas IDO1/IDO2 yog induced ntawm mRNA qib raws li stimulation nrog CTLA-4 immunoglobulin, tab sis tsis muaj protein ntau qhia thiab enzymatic kev ua ub no raug soj ntsuam nyob rau hauv txoj kev tshawb no. CTLA-4 yog lub hauv paus inhibitory regulator ntawm T cell proliferation thiab expansion, thiab CTLA-4 txoj kev los ntawm ligation rau CD80 thiab CD86 ntawm APCs yuav upregulate Foxp3 qhia induced los ntawm TGF-, coj Yuav ua li cas rau induction ntawm Tregs [221] Tsis tas li ntawd, CTLA-4 kev koom tes ntawm B7 ligands ntawm DCs, los ntawm qhov induction ntawm IDO1, tuaj yeem koom nrog kev saib xyuas ntawm peripheral kam rau ua [83]. Godin-Ethier thiab cov neeg ua haujlwm ua haujlwm [222] tau lees paub tias ob hom IDO1 / IDO2 thiab IDO protein tuaj yeem tswj hwm hauv tib neeg B lymphocytes hauv kev teb rau T cell signals; Txawm li cas los xij, lawv tau tshaj tawm tsuas yog tsis muaj zog / tsis muaj zog enzymatic los ntawm cov IDO-expressing hlwb, xaus lus tias IDO yuav tsis yog ib qho kev tiv thaiv kev tswj hwm uas siv los ntawm B lymphocytes los tswj lub cev tiv thaiv kab mob.

Nyob rau hauv sib piv rau Godin-Ethier li al. [222], Nouël thiab cov neeg ua hauj lwm [65] qhia txog txoj kev tswj hwm tshiab hauv B hlwb, kho los ntawm TGF- /IDO1 axis hauv CTLA-4- raws li kev nyob. Lawv tau pom thawj zaug uas CTLA-4 induced B-hlwb tuaj yeem tsim IDO1 thiab ua tau zoo induced regulatory B hlwb (regs), uas muaj peev xwm tsim Tregs, Tr1, thiab Th3 hlwb thaum cocultured nrog T hlwb, thaum lawv inhibit qhov induction ntawm Th1 hlwb. Cov kws sau ntawv no kuj tau qhia tias TGF / IDO1 axis plays lub luag haujlwm tseem ceeb hauv kev sib kho kom ruaj khov kev tswj hwm kev ua haujlwm hauv B hlwb, qhia txog cov kev xav tshiab rau kev tswj hwm yav tom ntej ntawm cov kab mob autoimmune [65]. Nws kuj tau pom tias IL-21 tuaj yeem ua rau Breg phenotype hauv tib neeg B hlwb, uas cuam tshuam nrog kev qhia ntawm cov tshuaj tiv thaiv kab mob: granzyme B, IL-10, thiab IDO1, thiab cov granzyme B. -dependent degradation ntawm TCR complex zeta-chain yuav suppress T-cells proliferation [223]. Ib yam li ntawd, cov hlwb mesenchymal stromal tuaj yeem txhawb txoj kev ciaj sia thiab kev loj hlob ntawm Bregs, thiab IDO1 ib feem koom nrog cov nyhuv no [224]. Piper et al. [225] tau txheeb xyuas AhR uas yog tus muaj feem cuam tshuam rau kev hloov pauv kev cai ntawm kev sib txawv thiab kev ua haujlwm ntawm IL-10- tsim Bregs. Lawv tau pom tias cov nas uas muaj AhR tsis txaus hauv Bregs txhim kho mob caj dab, cuam tshuam nrog kev txo qis hauv IL-10- ua Bregs ib yam li Tregs, thiab qhia qhov nce ntawm Th1 thiab Th17 cell subsets piv nrog cov nas, uas muaj AhR txaus Bregs. .

Cov kev tshawb fawb tsis ntev los no hauv vivo tau ua rau cov qauv ntawm autoimmunity qhia tias IDO2 tuaj yeem ua qhov txawv ntawm IDO1 lub luag haujlwm hauv B cell-mediated autoimmunity. Nws tau raug pom tias IDO2 yuav yog ib qho proinflammatory molecule uas ua rau autoreactive B cell teb. Qhov kev ua haujlwm pathogenic ntawm IDO2 tau piav qhia los ntawm Merlo thiab cov npoj yaig hauv KRN qauv ntawm autoimmune mob caj dab [226] thiab collagen-induced mob caj dab [227]. IDO2 knockout nas tso saib txo qis kev sib koom ua ke, txo qis hauv autoreactive B hlwb, thiab qis cov kab mob autoantibodies qib piv rau cov nas qus, qhia txog kev ua haujlwm ntawm IDO2 hauv autoantibody-mediated autoimmunity [226]. Kev tswj hwm ntawm IDO2- tshwj xeeb autoantibodies alleviated mob caj dab nyob rau hauv ob qho kev ywj pheej preclinical arthritis qauv, txo autoreactive T thiab B cell ua kom [227]. Ib yam li ntawd, tus antiIDO2 3DNA formulation amelioritis mob caj dab nyob rau hauv ib tug preclinical qauv [228]. Cov kev tshawb fawb tsis ntev los no ntawm pab pawg no siv ob npaug IDO1 / IDO2 knockout nas tau qhia qhov sib txawv ntawm IDO1 thiab IDO2 hauv kev tiv thaiv: IDO1 mediates T cell suppressive teebmeem (tej zaum los ntawm KYN ntau lawm), qhov IDO2, uas xyaum tsis tsim KYN, ua haujlwm ncaj qha hauv B. cell raws li ib tug proinflammatory mediator ntawm autoimmune txheej txheem. Yog li, IDO2 zoo li yog tus neeg ua si tseem ceeb hauv cov kab mob autoantibody-mediated autoimmunity los ntawm IDO1-kev ywj pheej mechanism [229].

4. Lub luag haujlwm ntawm IDO1 thiab KP Kev Ua Haujlwm hauv Autoimmunological Endocrinopathies

4.1. T1DM-Ib tug kab mob autoimmune nrog tsis meej pathophysiology

T1DM yog ib qho kab mob autoimmune, uas tshwm sim los ntawm kev puas tsuaj ntawm lub cev tiv thaiv kab mob uas ua rau kev xaiv kev puas tsuaj ntawm -cells hauv cov txiav thiab cuam tshuam hauv kev tso cov tshuaj insulin nrog qhov ua rau muaj kev cuam tshuam loj ntawm kev tswj glycemic. Hauv theem asymptomatic preclinical, kev nkag mus ntawm lub cev tiv thaiv kab mob mus rau pancreatic islets ntawm Langerhans tshwm sim, thiab cov txheej txheem no ua ntej hyperglycemia thiab kab mob pib. Txawm li cas los xij, qhov xwm txheej uas ua rau lub cev hloov pauv no tseem piav qhia tsis zoo [3,9,230].

Lub tswv yim classical rau txoj kev loj hlob ntawm T1DM yog tias nyob rau hauv cov tib neeg uas muaj caj ces predisposition, ua kom lub cev tiv thaiv kab mob (T-cells mediated autoimmune kab mob) los ntawm ib tug los yog ntau yam ib puag ncig ua rau kev puas tsuaj ntawm pancreatic -cells [231]. Qhov kev tshawb pom ntawm pancreatic islet cell autoantibodies qhia tawm tsam sib txawv autoantigens [11] ua ib qho kev sib cav hais tias -cells -specific proteins thiab peptides tau tsom los ntawm lub cev tiv thaiv kab mob [232]. Raws li kev pom zoo nrog qhov kev xav no, kev tswj hwm kev tiv thaiv kab mob peripheral zoo li tsis zoo hauv cov neeg mob T1DM, thiab kev cuam tshuam ntawm kev sib tham ntawm cov hlwb ntawm kev yoog raws thiab kev tiv thaiv hauv lub cev tuaj yeem ua kom nrawm lossis ncua kev txhim kho T1DM [24]. Txawm li cas los xij, kev siv tshuaj tiv thaiv kab mob hauv cov neeg mob uas muaj kev pheej hmoo siab ntawm kev tsim T1DM ncua kev loj hlob mus rau tus kab mob overt tab sis tsis tiv thaiv qhov pib ntawm T1DM [233].

Cov ntaub ntawv los ntawm cov kev tshawb fawb tsis ntev los no tau taw qhia lub luag haujlwm ntawm -cells ua tus tseem ceeb pab rau T1DM. Cov kab mob pancreatic tsis zoo tuaj yeem cuam tshuam rau kev ua haujlwm ntawm lub cev tiv thaiv kab mob zoo li no, uas nws yuav tsum tau tshem tawm cov hlwb tsis zoo. Ob peb qhov kev tshawb fawb tsis ntev los no zoo li txhawb qhov kev xav no, piv txwv li, cov kab mob pancreatic me me hauv cov neeg muaj kev pheej hmoo ntawm T1DM [234]. Qhov induction ntawm endoplasmic reticulum kev nyuaj siab tau raug lees paub tias yog ib qho tseem ceeb ntawm kev ua haujlwm rau -cells ua haujlwm tsis zoo nyob rau theem pib ntawm T1DM [235] thiab ua rau kev tsim ntawm lwm txoj kev "-cells centric hypothesis" [236]. Raws li qhov kev xav no, ib zaug -cell raug tawm tsam, ib puag ncig inflammatory yog tsim uas zoo li tso tawm cov proinflammatory cytokines ntxiv thiab chemokines los ntawm -cells, attracting ntau lub cev tiv thaiv kab mob. Hauv lub xeev inflammatory, -cells nthuav tawm ntau dua rau tib neeg leukocyte antigen (HLA) chav kawm I molecules, tsim cov teeb liab ntxiv rau cov seem cytotoxic CD8 ntxiv rau T hlwb, nws zaus nce hauv pancreata ntawm cov neeg mob T1DM piv nrog cov kev tswj hwm kev noj qab haus huv [ 237] ib.

Tregs, uas muaj lub luag haujlwm tseem ceeb hauv kev tawm tsam cov autoreactive T hlwb hauv kev noj qab haus huv, qhia txog kev txo qis hauv cov neeg mob T1DM [238], qhia tias kev tiv thaiv kab mob tsis txaus tuaj yeem yog vim li cas rau qhov muaj zog autoimmune teb los ntawm autoreactive T hlwb. Qhov kev xav no tau txais kev txhawb nqa los ntawm qhov tseeb tias cov neeg mob qog noj ntshav, kho nrog cov tshuaj tiv thaiv kab mob tiv thaiv kab mob txhawm rau txhim kho lub cev tiv thaiv kab mob thiab txo kev tiv thaiv kab mob, muaj kev pheej hmoo ntawm kev tsim T1DM vim tsis muaj kev tiv thaiv kab mob ua ke nrog kev ua kom lub cev tiv thaiv kab mob tawm tsam cov qog nqaij hlav [239 ]. Cov kev tshawb fawb tsis ntev los no los ntawm Li et al. [240] pom tias -cells tuaj yeem koom nrog T1DM kev loj hlob. Nyob rau hauv cov kev ntxhov siab, -cells tsim neoantigens thiab tuaj yeem kho qhov kev qhia ntawm MHC I / II thiab co-stimulatory molecules uas ib txwm pom los ntawm cov kws tshaj lij APCs. Lub subset ntawm APC-zoo li-cells ua haujlwm ua ke nrog pDCs ntawm qib cellular los qhib CD4 ntxiv thiab CD8 ntxiv rau T hlwb, pib cov lus teb thaum ntxov autoimmune ua rau T1DM txoj kev loj hlob. Qhov kev pom no, los ntawm txoj kev xav ntawm Roep li al. [236], rov mus saib qhov kev xav zoo li qub ntawm T1DM txoj kev loj hlob uas xav tias -cells tsuas yog cov neeg koom nrog thaum T1DM pib.

Kev sib xyaw ua ke ntawm ob txoj kev xav no tau tshaj tawm los ntawm Peters li al. [241], leej twg ntseeg tias T1DM yog qhov tshwm sim los ntawm kev sib koom ua ke ntawm kev ua haujlwm tsis zoo hauv cov hlwb thiab lub cev tiv thaiv kab mob, nrog rau qhov tsis xws luag hauv lub cev thiab kev tiv thaiv kab mob.

4.2. IDO1 thiab T1DM

Txawm hais tias muaj kev cuam tshuam IDO1-kev kho TRP cov metabolism tau raug pom nyob rau hauv cov kab mob autoimmune sib txawv [28], txog tam sim no tsis muaj cov ntaub ntawv ntau hauv cov ntaub ntawv muaj, hais txog lub luag haujlwm ntawm IDO1 thiab kev ua kom KP hauv autoimmunological endocrinopathies.

Ntawm cov paub endocrinopathies, T1DM yog ib qho kab mob autoimmune, uas qhov tseem ceeb ntawm IDO1 ua kom tau piav qhia tau zoo. Feem ntau, IDO1 tau lees paub tias yog tus tswj hwm kev tiv thaiv kab mob - nws tsis tsuas yog tsim cov tshuaj tiv thaiv kab mob kynurenines, tab sis nws kuj ua raws li lub teeb liab-transducing molecule, txhawb kev tiv thaiv kab mob hauv cov kab mob pathophysiological [242,243]. Txawm li cas los xij, lub xeev inflammatory uas qhia txog theem preclinical ntawm T1DM tuaj yeem cuam tshuam rau IDO1 protein qhia thiab kev ua haujlwm, ua rau nws lub luag haujlwm hauv kev tiv thaiv kab mob hauv lub txiav.

Cov kev tshawb fawb preclinical nyob rau hauv lub tshav pob ntawm T1DM yog nqa tawm nyob rau hauv txawv kev sim chaw siv cov qauv ntawm nonobese diabetic (NOD) nas. Tus qauv tau piav qhia raws li tus qauv prototypic ntawm autoimmune ntshav qab zib, uas zoo ib yam li T1DM hauv tib neeg [244]. Feem ntau ntawm cov poj niam nas feem ntau tuag ntawm hom 1 mob ntshav qab zib mellitus, qhia txog qhov pib ntawm insulitis hnyav txog li 4 lub lis piam ntawm hnub nyoog, uas cuam tshuam nrog T cell-mediated kev puas tsuaj ntawm pancreatic cell. Lub predisposition ntawm NOD nas los tsim autoimmunity yog qhov tshwm sim ntawm qhov tsis xws luag nyob rau hauv ob qho tib si peripheral thiab central tolerance mechanisms [245]. Ntau qhov txawv txav tau piav qhia hauv cov tsiaj no, xws li kev ua haujlwm tsis zoo ntawm APCs [246], lymphocyte accumulations nyob ib ncig ntawm cov islets ntawm Langerhans [247], los yog tiam thiab kev ua haujlwm ntawm Tregs hauv periphery [248]. Cov ntaub ntawv tau los ntawm tus qauv ntawm cov ntshav qab zib no qhia tau tias monocytes, macrophages, thiab pDC ua lub luag haujlwm tseem ceeb hauv kev txhim kho tus kab mob no [249].

Siv NOD nas thaum lub sij hawm prediabetes, Grohmann li al. [250,251] pom tias IFN- tsis ua kom muaj kev tiv thaiv kev tiv thaiv hauv lawv cov DCs. Cov txiaj ntsig no tau cuam tshuam nrog kev ua haujlwm qis IDO1 thiab cuam tshuam TRP catabolism los ntawm kev cuam tshuam ib ntus ntawm STAT1 txoj hauv kev ntawm intracellular signaling los ntawm IFN-, tshwm sim los ntawm peroxynitrite ntau lawm. Kev siv cov peroxynitrite inhibitor tau rov qab kho ob qho tib si haum TRP catabolism thiab kam rau ua rau cov nas. Muaj thawj cov ntawv ceeb toom ntawm kev sim ntshav qab zib, txuas rau kev tiv thaiv kab mob tsis zoo rau kev puas tsuaj rau TRP catabolism.

Ib qho kev soj ntsuam zoo sib xws tau ua los ntawm Fallarino thiab cov neeg ua haujlwm ua haujlwm [252], uas siv CTLA-4, lwm tus IDO1 inducer. Tom qab ntawd, Hosseini-Tabatabaei et al. [253] tau qhia meej txog qhov tshwm sim no, qhia tias qhov tsis zoo TRP metabolism tuaj yeem raug ntaus nqi los ntawm qhov tsis muaj peev xwm ntawm IFN- txhawm rau ntxias IDO1 kev qhia hauv DCs thiab fibroblasts ntawm cov tsiaj no los ntawm cov txheej txheem cuam tshuam txog kev puas tsuaj STAT1 phosphorylation hauv IDO1 txoj kev taw qhia. Kev tiv thaiv lub luag haujlwm ntawm IDO1 hauv kev txhim kho autoimmune ntshav qab zib kuj tau lees paub hauv tus qauv streptozocin-induced ntshav qab zib. Fallarino et al. [254] txheeb xyuas IDO1 yog qhov tseem ceeb ntawm Tus Xov Tooj Zoo li receptor 9 (TLR9) downstream effector hauv kev tswj hwm autoimmunity. Hauv cov tsiaj mob ntshav qab zib, qhov kev loj hlob ntawm tus kab mob tau ua nrog kev tswj hwm ntawm IDO1 hauv cov qog nqaij hlav pancreatic, thiab nws tau raug exacerbated los ntawm vivo tswj hwm ntawm IDO1 inhibitor. Hloov pauv, kev taw qhia los ntawm TLR9 induces IDO1 qhia nyob rau hauv splenic DCs thiab attenuated tus kab mob nyob rau hauv ib tug IDO1-dependent fashion. Txawm li cas los xij, TLR9-cov nas uas tsis muaj peev xwm tsim cov kab mob hnyav, nrog rau qhov tsis muaj IDO1 induction hauv cov qog nqaij hlav pancreatic [254].

Cov maneuvers muaj peev xwm ntawm kev khaws cia ntawm theem txaus ntawm IDO1 hauv NOD nas tau pom tias yuav rov qab kho autoantigen tshwj xeeb tolerogenesis los ntawm DCs hauv vivo. Pallotta et al. [255] pom tau hais tias kev tswj hwm ntawm IDO1 kev qhia thiab kev ua haujlwm enzymatic hauv pDC ntawm NOD nas tuaj yeem rov qab ua haujlwm, ua rau txo qis ntawm cov proinflammatory cytokines thiab kev tawm tsam ntawm kev nthuav qhia ntawm -cell autoantigens hauv vivo. Kev tswj hwm ntawm proteasome inhibitor-bortezomib-rau prediabetic NOD nas ua rau kev tiv thaiv kab mob ntshav qab zib pib los ntawm ib lub tswv yim cuam tshuam nrog kev rov qab los ntawm IDO1 qhia hauv pDCs los ntawm cov tsiaj no thiab rov txhim kho lub cev tiv thaiv kab mob rau pancreatic autoantigen [256]. Nyob rau hauv tib txoj kev, kev siv cov dermal fibroblasts nrog ruaj khov IDO1 qhia raws li kev kho ntawm tes hauv NOD nas los ntawm Zhang li al. [257] ua rau nce qib ntawm cov ntshav plasma KYN thiab muaj kev tiv thaiv kev tiv thaiv ntawm islet -cells, uas tau tiv thaiv toxicity induced los ntawm ob qho tib si autoreactive T hlwb thiab cov proinflammatory cytokines. Tsis tas li ntawd, lawv tau ua tiav inhibited CD8 ntxiv rau T hlwb, thiab Th17 hlwb thiab nce Tregs nyob rau hauv ntau yam kabmob ntawm NOD nas. Cov tshuaj txhaj tshuaj nrog ntau dua ntawm IDO1- qhia txog fibroblasts tuaj yeem kho cov normoglycemia hauv feem ntau ntawm NOD nas. Tsis tas li ntawd, kev hloov pauv ntawm IDO1- qhia cov islets tuaj yeem ua rau lub islet graft ciaj sia taus, thiab qhov kev tiv thaiv no yog los ntawm kev hloov kho hauv zos ntawm TRP catabolism [258,259].

Fallarino et al. [260] implanted peritoneally Sertoli hlwb, uas muab kev tiv thaiv hauv zos tiv thaiv kab mob hauv NOD nas, thiab pom kev tiv thaiv thiab thim rov qab ntshav qab zib thiab normalization ntawm glycemia hauv cov tsiaj no. Cov nyhuv no tau cuam tshuam nrog kev rov ua kom lub cev tiv thaiv kab mob, thiab nws yog nyob ntawm kev ua haujlwm ntawm TRP metabolism hauv xenografts, nce TGF- zais cia tom qab los ntawm autoantigen-specific Tregs sib txawv, thiab rov ua haujlwm ntawm -cells ua haujlwm hauv cov neeg mob ntshav qab zib. Kev tswj hwm ntawm tib neeg chorionic gonadotropin, lub cev xeeb tub tseem ceeb rau NOD nas inhibited qhov ua kom cov ntshav qab zib mellitus CD4 ntxiv thiab CD8 ntxiv rau T-cells hauv vitro, thiab kev loj hlob ntawm T1DM hauv vivo los ntawm kev txhawb nqa kev qhia ntawm IDO1 hauv DCs [261]. Hauv kev tshawb fawb tsis ntev los no, Lemos et al. [262] siv DNA nanoparticles, uas ua rau lub teeb liab adapter stimulator ntawm interferon genes (STING) thiab pom tau hais tias xws li kev kho mob nce IDO1 kev ua, uas tswj T hlwb tiv thaiv kab mob nyob rau hauv tus po, pancreas, thiab pancreatic lymph nodes ntawm NOD nas. Ntxiv mus, qhov kev kho no ncua T1DM pib thiab txo T1D tshwm sim thaum noj ua ntej kab mob pib. Txoj kev tshawb no kuj tau qhia tias NOD nas muaj STING polymorphism uas tej zaum yuav yog ib feem ntawm kev qhia tsis txaus interferon thiab IDO1 induction.

Ntawm qhov tod tes, cov pov thawj tshwm sim txhawb nqa tias -cells kev puas tsuaj los ntawm cov lus teb autoimmune tuaj yeem raug kho los ntawm AhR signaling. Hauv kev tshuaj xyuas tsis ntev los no, Yue et al. [263] tau piav qhia txog qhov muaj peev xwm cuam tshuam ntawm AhR ua kom nyob rau hauv T1DM pathogenesis, nthuav qhia nws cov txheej txheem tswj hwm hauv ntau hom kev tiv thaiv kab mob. Kev ua kom AhR los ntawm nws cov ligands tsis tsuas yog hloov kho txoj kev loj hlob thiab kev ua haujlwm ntawm cov tshuaj tiv thaiv kab mob, tab sis kuj txo cov kev qhia ntawm cov cytokines pro-inflammatory, thiab nyob rau hauv txoj kev no attenuates autoimmune teb thaum T1DM txoj kev loj hlob. Txawm li cas los xij, T1DM-ntaus NOD nas qhia txo qis kev ua haujlwm ntawm AhR [264], uas tsim qhov xav tau los tshawb nrhiav cov tshuaj tshiab, nyab xeeb uas tuaj yeem ua rau AhR thiab tawm tsam cov lus teb autoimmune.

Hauv cov ntsiab lus, tag nrho cov txiaj ntsig no qhia tias hauv T1DM-ntaus NOD nas qhov tsis txaus ntawm IFN- / IDO1 / AhR axis yog tam sim no, yog li kev sim ua kom muaj zog ntawm cov axis no hauv cov hlwb tsim nyog ntawm lub cev tiv thaiv kab mob tuaj yeem yog ib txoj hauv kev. tiv thaiv T1DM hauv cov qauv no, los ntawm kev kho dua ntawm kev tiv thaiv kab mob rau pancreatic autoantigens.

Cov tswv yim tiv thaiv kab mob tiv thaiv tau zoo tau siv los tiv thaiv T1DM pib. Rau lub hom phiaj no, cov tshuaj tiv thaiv chimeric uas txuas cov immuno-stimulatory molecules nrog autoantigens los txhim kho kev siv tshuaj tiv thaiv. Kev sib txuas ntawm tus kab mob cholera toxin B-subunit rau cov ntshav qab zib autoantigen proinsulin tsim cov fusion protein, uas tuaj yeem tiv thaiv T1DM [265-267]. Kev txhaj tshuaj tiv thaiv qhov ncauj nrog cov tshuaj tiv thaiv no tau txais txiaj ntsig zoo-kev puas tsuaj ntawm tes thiab kev kho mob ntshav qab zib hauv cov neeg laus NOD nas [265,267]. Tsis tas li ntawd, tshuaj tiv thaiv-induced IDO1 qhia hauv DCs tau cuam tshuam nrog kev cuam tshuam ntawm kev tiv thaiv kab mob [266,268]. Cov txiaj ntsig sib piv tau txais los ntawm pab pawg ntawm Ghazarian li al. [269] uas tau pom tias kev ua kom tsis muaj zog ntawm cov neeg tua neeg tsis zoo T (iNKT) cov hlwb thaum lub sijhawm kis kab mob los ntawm pancreatic enterovirus- Coxsackievirus B4-hauv ib pawg ntawm proinsulin 2- tsis muaj NOD nas tuaj yeem tiv thaiv kev txhim kho ntshav qab zib. Lawv tau pom tias thaum mob ntshav qab zib mellitus tshwm sim hauv cov nas no, kev nkag mus ntawm pancreatic islets los ntawm inflammatory macrophages, ua rau cov qib pro-inflammatory cytokines (IL-6, IL-1, TNF-) tau tshwm sim, uas yog. cuam ​​tshuam nrog kev ua kom T hlwb tsim tawm los tiv thaiv islet autoantibodies.

Txawm hais tias tus kab mob kis nws tus kheej tau nrawm rau kev txhim kho cov ntshav qab zib, qhov muaj cov hlwb iNKT thaum lub sijhawm no ua rau infiltrated macrophages los qhia ntau cov enzymes suppressive, ntawm cov IDO1 txaus los tiv thaiv cov islet T cell teb thiab tiv thaiv T1DM. Txoj kev tshawb no qhia tias IFN-, tus muaj zog activator ntawm IDO1 qhia, tuaj yeem ua lub luag haujlwm tiv thaiv lossis tshem tawm hauv kev txhim kho ntshav qab zib. Qhov muaj zog IFN- tso tawm ntxov tom qab kis tus kab mob upregulates IDO1 kev qhia kom txo qis tus kab mob uas ua rau mob. Txawm li cas los xij, yog tias lub sijhawm no iNKT hlwb tsis ua haujlwm, kev tsim cov cytokines pro-inflammatory tuaj yeem ua rau kom muaj kev nrhiav neeg ua haujlwm thiab ua kom muaj cov kab mob T hlwb, tsim IFN-. Hauv cov xwm txheej no, IDO1 tsis tau hais tawm hauv lub txiav, thiab IFN- ntau lawm yuav ua rau -cells puas [269].

Lwm lub tswv yim siv los tiv thaiv kev txhim kho ntawm T1DM yog hloov kho lub plab microbiota. Dolpady et al. [270] muab tshuaj Lactobacillaceae-enriched probiotic rau NOD nas thiab pom tias kev hloov kho ntawm plab microbiota inhibited IL-1 qhia, thaum nws txhim kho qhov tso tawm ntawm IDO1 thiab IL-33 los ntawm inflammasome. Cov kev hloov kho ntawm txoj hnyuv microenvironment txhawb kev sib txawv ntawm tolerogenic DCs nrog kev txo qis ntawm Th1 thiab Th17 cell expansion nyob rau hauv cov hnyuv mucosa thiab nyob rau hauv lub pancreatic lymph nodes. Cov txiaj ntsig no tau taw qhia qhov kev kho tshiab muaj peev xwm siv cov probiotics los tiv thaiv autoimmunity thiab tiv thaiv T1DM.

Kev soj ntsuam ua rau tsiaj qauv tau lees paub thaum kev tshawb fawb soj ntsuam hauv cov neeg mob T1DM. Hauv tib neeg, IDO1 kev qhia thiab kev ua haujlwm tau paub tias muaj qhov sib txawv ntawm ib tus neeg sib txawv, feem ntau tshwm sim los ntawm ib qho nucleotide polymorphisms (SNPs) hauv cov enzyme gene, tshwj xeeb tshaj yog nyob rau hauv cov kab mob pathological [271,272]. Orabona et al. [273] pom tias, hauv cov menyuam yaus uas muaj T1DM, IDO1 qhia thiab cov protein ntau tsawg lossis tsis muaj nyob rau hauv peripheral ntshav mononuclear hlwb (PBMCs) teb rau IFN- . IDO1 qhov tsis xws luag cuam tshuam nrog ntau dua IL-6 receptor qhia, thiab cov menyuam yaus nrog SNPs hauv IDO1 yog qhov muaj feem pheej hmoo ntawm kev tsim T1DM. Hauv T1DM cov neeg mob sib koom xws li IDO1 haplotype, incubation of PBMCs in vitro with tocilizumab, humanized antibody that blocks IL-6 receptor, cawm IDO1 kev ua. Hauv tib txoj kev tshawb fawb, kev kho mob ntawm NOD nas nrog tocilizumab normalized glycemia ntawm IDO1- cov txheej txheem nyob ntawm. Yog li, kev ua haujlwm SNPs ntawm IDO1 tau cuam tshuam nrog kev puas tsuaj TRP catabolism hauv tib neeg T1DM, thiab cov nyhuv kho ntawm tocilizumab xav tau qhov kev qhia tsis zoo ntawm IDO1. Anquetil et al. [274] kuj tau tshaj tawm qhov tsis txaus IDO1 qhia hauv tib neeg-hlwb ntawm cov neeg mob T1DM piv rau kev tswj hwm kev noj qab haus huv. IDO1 qhia feem ntau muaj nyob rau hauv cov hlwb tsim cov tshuaj insulin thiab ze li ntawm cov islets uas tsis muaj insulin hauv tib neeg cov ntaub so ntswg, tshwj xeeb tshaj yog nyob rau hauv cov neeg mob uas muaj ntau yam autoantibodies tawm tsam - hlwb. Ntxiv mus, qhov kev poob zuj zus ntawm IDO1 qhia tau pom thaum lub sij hawm T1DM, nrog kev poob qis ntawm IDO1 ib zaug xwb ua ntej -cells puas tsuaj [274]. Zos et al. [275] tau piav qhia thiab qhia txog cov pej xeem ntawm tib neeg MDSCs, hu ua fibrocytic MDSCs, uas tau hloov pauv ntawm DCs, macrophages, thiab fibrocytes. Qhov no MDSC subset txhawb Tregs sib txawv ntawm naive CD4 ntxiv rau T hlwb thiab induces normoglycemia nyob rau hauv ib tug xenogeneic nas qauv ntawm T1DM. Txhawm rau siv lawv cov protolerogenic muaj zog, fibrocystic MDSCs xav tau kev sib cuag ncaj qha nrog cov kab mob T hlwb, uas ua rau kev nthuav tawm thiab tso tawm ntawm IDO1.

Hauv monocytes thiab pDC muab tau los ntawm cov ntshav peripheral ntawm T1DM cov neeg mob, Badal thiab cov npoj yaig [276] pom kev txo qis ntawm IDO1, uas tau ua pov thawj tias cov hlwb no tau txo qis tolerogenic peev xwm piv rau lawv cov kev noj qab haus huv ib txwm muaj. Hauv qhov sib piv, pDCs ntawm tib pab pawg T1DM no tau pom ntau zaus ntawm pDCs qhia IFN- dua li kev tswj hwm kev noj qab haus huv, thaum cov monocytes muaj qhov sib piv los tswj cov zaus ntawm IFN- - qhia cov hlwb. Interestingly, ua raws li nyob rau hauv vitro stimulation nrog tus kheej-DNA los ntawm cov tuag-cells thiab antimicrobial peptide LL37 (DNA-LL37) complexes, ob leeg monocytes thiab pDCs los ntawm T1DM cov neeg mob tau pom ntau dua IFN-kev qhia. Tsis tas li ntawd, lub peev xwm poststimulatory rau kev nthuav qhia antigen thiab co-stimulatory muaj peev xwm ntawm cov hlwb yog siab dua nyob rau hauv T1DM pawg tshaj li ntawm kev tswj, thiab, thaum coculture, lawv muaj peev xwm mus qhib autologous CD4 ntxiv rau T hlwb thiab induce apoptosis ntawm kab lis kev cai hlwb. Cov txiaj ntsig no txhawb nqa lub luag haujlwm tsis txaus ntseeg ntawm kev cuam tshuam ntawm kev sib npaug ntawm cov hlwb uas koom nrog hauv lub cev tiv thaiv kab mob, uas tuaj yeem cuam tshuam ob qho tib si kev tiv thaiv kab mob los ntawm kev qhia ntawm IDO1 lossis tuaj yeem cuam tshuam rau cov phenotype los ntawm kev qhia ntawm IFN- nyob rau qee qhov xwm txheej.

Ua tib zoo xav txog tag nrho cov ntaub ntawv no los ntawm cov qauv tsiaj thiab tib neeg kev tshawb fawb, nws zoo nkaus li tias kev kho dua tshiab ntawm IDO1 immunoregulatory mechanisms yuav muaj txiaj ntsig zoo rau cov neeg mob T1DM.

4.3. IDO1 thiab autoimmune thyroiditis

Hashimoto tus kab mob thiab Graves' kab mob yog cov feem ntau thiab tsis tshua muaj ntau hom ntawm autoimmune thyroiditis, uas ua rau thyrocyte tuag los yog hyperfunction, feem [4]. Txog tam sim no, tsuas yog qee qhov kev tshawb fawb muaj nyob rau hauv lub luag haujlwm ntawm IDO1 thaum pib ntawm cov kab mob no tau tshawb xyuas.

Hauv cov neeg mob uas muaj GD, qhov piv ntawm cov ntshav KYN rau TRP, nrog rau IDO1 qhia hauv B hlwb thiab DCs, tau nce ntxiv piv rau cov kev noj qab haus huv. CD4 ntxiv rau T hlwb muab tau los ntawm cov neeg mob GD tau txhim kho tryptophanyl-tRNA synthetase (TTS) kev qhia thiab lawv qhov kev loj hlob tsis raug cuam tshuam thaum muaj IDO1- qhia DCs. Hauv qhov sib piv, CD4 ntxiv rau T hlwb tau txais los ntawm kev tswj hwm kev noj qab haus huv tau qis TTS qhia, thiab lawv qhov kev loj hlob tau raug txwv nyob rau hauv cov xwm txheej zoo sib xws [277]. Vim hais tias TTS tuaj yeem ua haujlwm tiv thaiv IDO1-kev tiv thaiv kab mob sib kis los ntawm TRP reservoir tsim, cov kws sau ntawv tau txiav txim siab tias TTS nthuav qhia ntau ntxiv hauv CD4 ntxiv rau T hlwb tuaj yeem tiv thaiv IDO1-kev kho cov tshuaj tiv thaiv kab mob sib kis, txuas kev cuam tshuam TRP cov metabolism hauv cov txheej txheem pathogenic koom nrog. hauv GD kev txhim kho. Txawm li cas los xij, hauv lwm txoj kev tshawb fawb, qhov qis dua KYN rau TRP piv thiab qhov nce ntxiv hauv TRP qib tau kuaj pom hauv sera los ntawm cov neeg mob HT thiab GD piv rau kev sib tw tswj [278]. Cov neeg mob, feem ntau yog cov neeg muaj tus kab mob hnyav, qhia txog qhov txo qis ntawm peripheral pDCs thiab kev qhia tsis zoo ntawm ntau lub cev tiv thaiv kab mob, suav nrog IDO1 los ntawm cov hlwb no. Thaum ntau pDCs thiab qhov txo qis ntawm kev tswj hwm molecules tau kuaj pom hauv cov thyroid cov ntaub so ntswg los ntawm cov neeg mob no. Cov ntaub ntawv no qhia tias qhov txawv txav thiab phenotype ntawm pDCs tuaj yeem ua rau cov kab mob autoimmune thyroiditis.

Interestingly, cov tsos mob ntawm GD, zoo ib yam li lwm yam kab mob autoimmune, zoo ameliorate thaum cev xeeb tub thiab rov tshwm sim tom qab yug me nyuam, vim hais tias placenta syncytiotrophoblasts tuaj yeem tsim cov tshuaj tiv thaiv kab mob, suav nrog IDO1, uas txwv kev tiv thaiv kab mob. Hauv qhov sib piv, tsis muaj kev hloov pauv hauv HT tshwm sim thaum cev xeeb tub, txawm hais tias koob tshuaj levothyroxine yuav tsum tau nce ntxiv thaum cev xeeb tub, zoo ib yam hauv txhua hom hypothyroidism [279].

Coppola et al. [280] soj ntsuam hauv vitro lub peev xwm ntawm tib neeg fibroblast-zoo li limbal qia hlwb, lub cev tiv thaiv kab mob phenotype, kom siv tshuaj tiv thaiv kab mob ntawm PBMCs los ntawm poj niam HT cov neeg mob thiab tswj kev noj qab haus huv. Tom qab raug rau Th1 cytokines, cov hlwb no qhia cov cytokines sib txawv, suav nrog IDO1, tswj lawv cov phenotype tsis zoo rau MHC chav kawm II thiab costimulatory molecules. Thaum lub sij hawm coculture, cov hlwb no suppressed proliferation nyob rau hauv noj qab haus huv activated PBMCs, whereas lub Th imbalance ntawm autoreactive T hlwb los ntawm HT cov neeg mob tau tag nrho rov qab. Cov txiaj ntsig no tau qhia txog qhov tsis tsim nyog ua kom tsis zoo ntawm autoreactive T lymphocytes hauv cov kab mob inflammatory milieu generated hauv HT, thiab qhia tias kev tsim ntawm ib puag ncig tolerogenic tuaj yeem thim rov qab cov kab mob.

Kev sim autoimmune thyroiditis (EAT) tau kawm siv tus nas hu ua tus qauv NOD-H2h4 uas txhim kho nws tus kheej. Cov tsiaj no poob qhov kev loj hlob ntawm cov ntshav qab zib, tab sis kis tau cov thyroiditis. autoimmune thyroiditis nyob rau hauv cov nas no yog T-cell-mediated autoimmune kab mob uas rhuav tshem cov thyroid follicles [281].

Nws tau raug pom tias CTLA-4 blockade exacerbated autoimmune thyroiditis nyob rau hauv NOD-H2h4 nas thiab induced ib tug muaj zog qhia ntawm IDO1 nyob rau hauv nas thyroid caj pas thiab peripheral APCs. Ntxiv mus, qhov kev nthuav qhia IDO1 hnyav kuj tau pom nyob rau hauv cov thyroid caj pas ntawm cov neeg mob metastatic melanoma, uas tau txais kev kho mob nrog CTLA-4 thaiv cov tshuaj tiv thaiv. Cov kws sau ntawv tau txhais qhov no IDO1 nce raws li kev tswj hwm kev tswj hwm, tiv thaiv kev mob ntau dhau los ntawm CTLA-4 thaiv. Ib yam li ntawd, NOD-H2h4 nas tau tsim ib qho kev txo qis ntawm cov thyroiditis thaum txhaj tshuaj adenovirus uas qhia txog IDO1 ncaj qha rau hauv cov thyroid caj pas tom qab pib ntawm iodine supplementation hauv dej haus. Lub zos qhia ntawm no immunoregulatory molecule zoo tiv thaiv cov thyroid caj pas los ntawm autoimmune tawm tsam tab sis tsis cuam tshuam rau lub cev tiv thaiv kab mob [282]. Tsis ntev los no, Qiu et al. [283] tau sau tseg lub luag haujlwm ntawm IDO1-induced Tregs expansion hauv Prunella vulgaris-mediated attenuation ntawm kev sim autoimmune thyroiditis hauv nas. Lawv tau pom tias kev tswj hwm ntawm cov tshuaj ntsuab no ua rau IDO1 mRNA thiab cov protein qhia nyob rau hauv tus po thiab txoj hnyuv, nce ntshav hauv KYN / TRP piv thiab tsim tawm IL-10 thiab TGF-, thiab txhawb kev nthuav dav ntawm splenic Tregs. Interestingly, IDO1 mRNA qib thiab KYN / TRP piv tau piv ntawm kev tswj kev noj qab haus huv thiab cov nas tsis kho nrog EAT. Raws li tau piav qhia los ntawm cov kws sau ntawv, qhov kev txhim kho IDO1 qhov kev qhia yog ib qho kev them nyiaj, uas cov nas nrog EAT tau sim txo qhov kev tiv thaiv tus kheej thaum pib tus kab mob. Cov txheej txheem tiv thaiv kev tiv thaiv no tau zoo li tsis muaj zog thaum lub sij hawm EAT txoj kev loj hlob, ua rau txo qis hauv IDO1 qhia rau qib pom hauv cov tsiaj noj qab haus huv.

Nyob rau hauv lub teeb ntawm ob peb cov kev tshawb fawb saum toj no, nws zoo li hais tias lub zos IDO1 qhia tau zoo tiv thaiv cov thyroid caj pas los ntawm autoimmune tawm tsam. Qhov kev xav no tau txhawb nqa los ntawm kev tshawb fawb txog cov thyroid carcinomas cov ntaub so ntswg thiab cov thyroid carcinoma cell kab [284]. IDO1 gene qhia tau siab dua hauv cov thyroid carcinoma cov ntaub so ntswg piv nrog cov thyroid ib txwm, thiab nws tau txuam nrog Foxp3 ntxiv rau Tregs ntom ntom hauv cov qog microenvironment. IDO1 kuj tau hais tawm hauv tib neeg cov kab mob qog noj ntshav hauv vitro, thiab hauv kab xov tooj ntawm tes nrog qhov siab tshaj plaws IDO1 qhia, qhov nce KYN kuj tau kuaj pom hauv cell kab lis kev cai nruab nrab, qhia txog kev ua haujlwm ntawm IDO1. Lub coculture ntawm no cell kab nrog activated T lymphocytes ua rau lub blocking ntawm lymphocyte proliferation, whereas Tregs txawv tau nce. Cov tshuaj tiv thaiv kab mob tau hais los saum toj no tau kho los ntawm qhov ua tau zoo-KYN.

Raws li peb qhov kev paub zoo tshaj plaws, nyob rau hauv cov ntaub ntawv muaj, tsis muaj cov ntaub ntawv tam sim no hais txog qhov tseem ceeb ntawm IDO1-KP ua kom muaj kev sib haum xeeb hauv qhov pib thiab kev loj hlob ntawm lwm yam autoimmune endocrinopathies, tshwj tsis yog txoj kev tshawb fawb los ntawm Gupta li al. [285], ua qauv qhia IDO1 reactivity hauv cov kab mob pancreatic ntawm cov neeg mob uas muaj hom 2 autoimmune pancreatitis.

5. Cov lus xaus thiab cov kev xav yav tom ntej

Cov kab mob autoimmune feem ntau tshwm sim los ntawm kev tsis txaus siab rau tus kheej, uas ua rau lub cim ntawm tus kheej-reactive lymphocytes thiab tsim cov autoantibodies uas ua rau cov ntaub so ntswg puas. IDO1-kev ua kom sib haum xeeb ntawm KP tau ua pov thawj tseem ceeb hauv kev sib txuas cov txheej txheem hauv nruab nrog cev thiab hloov pauv lub cev tiv thaiv kab mob, xws li inhibition ntawm T cell teb rau antigenic stimulation, modulation ntawm APC functions, tiam thiab kev saib xyuas ntawm Treg suppressor kev ua, thiab inhibition ntawm proinflammatory cytokines ntau lawm. Yog li, kev tswj hwm IDO1 / KYN / AhR axis zoo li yog lub tswv yim zoo los kho ntau yam kab mob autoimmune, suav nrog autoimmune endocrinopathies. Txawm hais tias feem ntau ntawm cov kev tshawb fawb qhia txog kev sib raug zoo ntawm kev hloov pauv ntawm TRP metabolism ntawm KP thiab kev tiv thaiv kab mob tau ua nyob rau hauv vitro lossis sim tsiaj cov qauv, ntau cov ntaub ntawv sau qhia tias lawv tuaj yeem hloov mus rau tib neeg. Qhov no qhib qhov muaj txiaj ntsig zoo rau kev siv tshuaj kho mob ntawm IDO1 inducers nyob rau hauv cov xwm txheej, qhov twg cov tshuaj tiv thaiv kab mob tsis ua haujlwm, xws li autoimmune endocrinopathies. Ib leeg, lossis ua ke nrog lwm cov kev kho mob uas twb muaj lawm, txoj hauv kev no tuaj yeem tsim kev sib xyaw ua ke tshiab, uas yuav koom nrog ntau yam ntawm cov txheej txheem pathogenic, muab kev tiv thaiv ntau dua thiab muaj peev xwm tiv thaiv kab mob.

Tus sau kev koom tes:

Kev xav, AK; kev sau ntawv—kev npaj ua ntej, AK; kev pom, AK; kev sau ntawv- tshuaj xyuas thiab kho, IK Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.

Nyiaj txiag:

Qhov kev tshawb fawb no tsis tau txais nyiaj txiag sab nraud.

Institutional Review Board Statement:

Tsis siv tau.

Cov Lus Qhia Txog Kev Pom Zoo:

Tsis siv tau.

Cov ntaub ntawv muaj nyob:

Tsis siv tau.

Kev tsis sib haum xeeb ntawm kev txaus siab:

Cov kws sau ntawv tshaj tawm tsis muaj kev sib cav txog kev txaus siab.

Cov ntaub ntawv

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