Lub luag hauj lwm ntawm Th17 Cells/IL-17A nyob rau hauv AD, PD, ALS Thiab Cov Tswv Yim Kho Kev Kho Mob Targeting Ntawm IL-17A Part 1

Abstract

Cov kab mob neurodegenerative yog ib pawg ntawm cov teeb meem uas tshwm sim los ntawm kev poob qis ntawm qee cov neeg ntawm neurons, uas thaum kawg ua rau tsis ua haujlwm. Cov kab mob no suav nrog Alzheimer's disease (AD), Parkinson's disease (PD), thiab amyotrophic lateral sclerosis (ALS).

Cov kab mob neurodegenerative yog ib qho kev nyiam. Raws li cov neeg muaj hnub nyoog, ntau thiab ntau tus neeg pib mob siab rau qhov cuam tshuam ntawm tus kab mob ntawm kev nco. Cov kab mob neurodegenerative yog ib hom kab mob uas tshwm sim los ntawm kev tuag ntawm cov neurons, uas ua rau ib feem ntawm lub hlwb poob haujlwm. Kev tsis zoo ntawm tus kab mob no yuav cuam tshuam ncaj qha rau tib neeg lub peev xwm kev txawj ntse, rhuav tshem kev sib raug zoo, thiab ua rau muaj kev poob qis hauv lub neej zoo.

Txawm li cas los xij, peb tseem muaj txoj hauv kev los tiv thaiv lossis txo tus kab mob no. Ib txoj hauv kev zoo tshaj plaws yog kev tawm dag zog lub plawv thiab ua pa tsis tu ncua txhawm rau txhim kho cov pa oxygen thiab ua kom cov ntshav txaus. Tsis tas li ntawd, kev noj zaub mov kom zoo thiab pw tsaug zog txaus kuj tseem ceeb heev. Kev noj qab nyob zoo yuav yog ib txoj hauv kev zoo tshaj plaws los tiv thaiv cov kab mob neurodegenerative.

Tsis tas li ntawd, peb tuaj yeem siv peb lub hlwb los ntawm kev kawm thiab kev xav tas li kom lawv nquag thiab tiv thaiv kev degeneration. Peb kuj tuaj yeem koom nrog kev sib raug zoo, mus ncig, kawm cov lus tshiab lossis kev txawj ntse, thiab lwm yam dej num los txhawb lub hlwb thiab ua kom nco. Qee zaum, kev nco kuj tuaj yeem ntxiv dag zog los ntawm kev cob qhia kev nco, xws li kev ua kom peb lub peev xwm nco tau los ntawm kev rov nthuav tawm cov ntaub ntawv thiab saib xyuas hauv peb lub neej niaj hnub, nco ntsoov nws, thiab lwm yam.

Txawm hais tias cov kab mob neurodegenerative loj hlob sai, peb tuaj yeem tswj lawv mus rau qhov loj. Hloov chaw, peb yuav tsum tsom mus rau kev txhim kho peb lub peev xwm thiab kev nco qab kom ntseeg tau tias peb lub neej zoo dua thiab ua tiav ntau dua. Yog li ntawd, peb yuav tsum xyuam xim rau peb lub cev thiab lub hlwb kev noj qab haus huv, tiv thaiv cov kab mob neurodegenerative, thiab rov nco peb cov neeg laus los ntawm kev ua neej nyob thiab noj qab haus huv, kev tawm dag zog, thiab kev kawm. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob yam, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov khoom noj txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub 10 txoj hauv kev los txhim kho kev nco

Kev tiv thaiv kab mob dysregulation yog ib qho ntawm cov yam ntxwv ntawm neurodegeneration. Tsis ntev los no, tau muaj kev txaus siab rau lub luag haujlwm tshwj xeeb ntawm T pab Th 17 hlwb thiab Interleukin -17A (IL-17A), qhov tseem ceeb tshaj plaws cytokine ntawm Th 17 hlwb, nyob rau hauv lub pathogenesis ntawm lub hauv paus. paj hlwb (CNS) ntawm cov kab mob neurodegenerative.

Hauv txoj kev tshawb fawb tam sim no, peb tau sau cov kev paub tam sim no txog kev ua haujlwm ntawm Th17/IL-17A, lub cev ntawm Th17/IL-17A hauv cov kab mob, thiab kev koom tes ntawm Th17/IL-17 A hauv AD, PD, thiab ALS.
Peb kuj tseem hloov kho qhov kev tshawb pom ntawm IL-17A-targeting tshuaj raws li cov tshuaj tiv thaiv kab mob tiv thaiv kab mob rau cov kab mob neurodegenerative.

Txawm hais tias cov txheej txheem tshwj xeeb ntawm Th17/IL-17A nyob rau hauv pab pawg kab mob no tseem muaj teeb meem, nthuav tawm txoj hauv kev molecular ntawm Th17 / IL-17A hauv neurodegeneration tso cai rau kev txheeb xyuas cov hom phiaj tsim nyog los hloov cov txheej txheem cellular. Cov kws kho mob tsom rau IL-17Ib tug yuav sawv cev rau cov tshuaj tiv thaiv neurodegenerationdrugs tshiab.

Keywords: TH17, IL-17A, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Targeted therapy.

Keeb kwm

Cov kab mob neurodegenerative yog ib pawg ntawm cov teeb meem uas tshwm sim los ntawm kev poob qis ntawm qee cov neeg ntawm cov neurons, uas thaum kawg ua rau tsis ua haujlwm. Cov kab mob no suav nrog Alzheimer's disease (AD), Parkinson'sdisease (PD), thiab amyotrophic lateral sclerosis (ALS).

Tam sim no, kev kho mob ntawm cov kab mob neurodegenerative tseem nyuaj heev, yog li nws tseem ceeb heev kom nkag siab txog cov txheej txheem pathophysiological ntawm cov kab mob neurodegenerative.

Cov kab mob neurodegenerative yog tus cwj pwm los ntawm kev xaiv qhov cuam tshuam ntawm qee cov paj hlwb, sib txawv ntawm cov protein sib xyaw, thiab cov lus teb tsis zoo ntawm lub cev [1]. Lub pathogenesis ntawm neurodegeneration yog kev sib koom ua ke ntawm ntau yam, thiab neuroinflammation yog suav tias yog ib feem ntawm qhov ua rau neurodegeneration.

Neuroinflammation yog tus cwj pwm los ntawm kev nce qib ntawm cov kab mob inflammatory mediators lossis cytokines hauv centralnervous system (CNS) parenchyma [2]. Tsis ntev los no, tau muaj kev txaus siab rau lub luag haujlwm tshwj xeeb ntawm T helper 17 (TH17) cells thiab interleukin -17A (IL-17A), qhov tseem ceeb tshaj plaws cytokine ntawm T 17 hlwb, nyob rau hauv lub pathogenesis ntawm lub hlwb. CNSof cov kab mob neurodegenerative.

Cov kev tshawb fawb tau pom tiasIL-17Ib qho ua rau ntau lub hlwb nyob hauv nruab nrab ntawm lub paj hlwb, txhim kho cov lus teb neuroinflammatory, thiab ua lub luag haujlwm pathogenic hauv ntau yam kab mob neurodegenerative [3].

Txawm li cas los xij, lub luag haujlwm ntawm TH17/IL-17A nyob rau hauv cov kab mob neurodegenerative tseem tsis meej thiab tsis sib xws.Yog li ntawd, peb tau sau cov kev paub tam sim no txog kev ua haujlwm ntawm T17 / IL-17A, physiology ntawm T17 / IL{{ 5}}Ain kab mob, thiab kev koom tes ntawm T17/IL-17A hauv AD, PD, thiab ALS. Peb kuj hloov kho qhov kev tshawb pom ntawm IL-17A-targeting tshuaj raws li cov tshuaj tiv thaiv kab mob tiv thaiv kab mob rau cov kab mob neurodegenerative.

Biology ntawm Th17 hlwb thiab IL-17A

T17 hlwb raug lees paub hauv xyoo 2005 raws li cov kab mob sib txawv ntawm T pab (T) CD4+ hlwb [4, 5]. Qhov sib txawv ntawm T17 hlwb yuav tsum muaj kev txhawb nqa nrog qee yam cytokines, suav nrog IL-6, IL-23, IL-1, transforming growthfactor- (TGF- ), thiab IL-21 [6– 14] ib.

Cov cytokines no tuaj yeem ua rau JAK-STAT3 axis, thiab nce qhov kev qhia ntawm kev hloov pauv, suav nrog retinoic orphan receptor (ROR) t thiab ROR [15–19].

T17 hlwb yuav ua tiav cov kab mob muaj peev xwm nyob rau hauv kev txhawb nqa los ntawm proinflammatory cytokines IL-6, IL-23, thiab IL-1 , whereascytokine TGF- tsav txoj kev loj hlob ntawm kev tiv thaiv T17 hlwb los ntawm kev tsim cov tshuaj tiv thaiv. -inflammatory cytokine IL-10 [19–21].

IL-21 txhawb nqa kev nthuav dav ntawm T17 hlwb hauv lub voj autocrine [22]. IL-17A, thawj zaug hu ua cytotoxic T-lymphocyte antigen (CTLA)-8 thiab cloned thawj zaug hauv 1993, yog tus kos npe cytokine ntawm T17 hlwb [23], thiab nws tau piav raws li RNA transcripthomologous rau tus kab mob Herpesvirus Saimiri noob.

Xyoo 1995, IL-17-binding receptor yog thawj zaug tshaj tawm [24, 25]. Dhau li ntawm T17 hlwb, lwm qhov chaw sib txawv kuj tsimIL-17A, suav nrog δT, T-cell receptor (TCR){{7 }} naturalT17, natural killer T (NKT), pawg 3 innate lymphoidcells (ILC3), Paneth cells, macrophages, thiab microglia hauv CNS [26–29].

Kev ua haujlwm ntawm Th17 hlwb thiab IL-17A

Ua ntej, T17 hlwb tuaj yeem ua rau muaj kev phom sij txaus ntshai, nrhiav thiab qhib cov neutrophil granulocytes, txhim kho kev qhia ntawm cov tshuaj tiv thaiv kab mob, thiab txhawb kev tshem tawm cov kab mob extracellular thiab fungi [30, 31].

IL-17A muaj lub peev xwm tseem ceeb los txhawb kev qhia ntawm chemokines thiab cytokines [3]. Thechemokines, suav nrog CXC motif ligand 1 (CXCL1), CXCL2, thiab CXCL8 tuaj yeem nyiam cov hlwb myeloid rau cov ntaub so ntswg raug mob [32].

Cov cytokines, suav nrog granulocyte colony-stimulating factor (G-CSF) thiab IL-6, tuaj yeem txhawb nqa myeloid-driven innate o [33]. Thepro-inflammatory cytokines thiab antimicrobial peptidesare upregulated los muab ib tug synergistic nyhuv ntawm limiting fungal overgrowth [34, 35]. Piv txwv li, nyob rau hauv daim tawv nqaij noj qab nyob zoo, IL-17Ib qho kev tsim tawm yog induced los ntawm commensal microflorato muab kev tiv thaiv kab mob fungal [23].

Thaum lub epithelial barrier ntawm daim tawv nqaij raug puas tsuaj los ntawm kev raug mob, IL-17Ib tug tuaj yeem txhawb kev loj hlob ntawm cov hlwb epithelial thiab tshem tawm cov kab mob pathogenic [36].

Nyob rau hauv txoj hnyuv, theIL-17Kev tsim khoom yog tsav los ntawm microbiota los ntawm lub zos epithelium los muab cov tshuaj tua kab mob, thiab nws tuaj yeem pab tswj dysbiosis thiab tswj qhov sib npaug ntawm homeostatic hauv plab [37, 38]. Nyob rau hauv laminapropria ntawm txoj hnyuv me, T17 hlwb tuaj yeem kho qhov kev tiv thaiv ntawm cov kab mob pathogenic microorganisms.

Nyob rau hauv lub hlwb ntawm cov neeg mob AD, Malassezia hom, ib qho ntawm cov kab mob feem ntau pom tau tuaj yeem ua rau neuroinflammation los ntawm kev ua kom T17 tiv thaiv kab mob [39].

Thib ob, T17 hlwb thiab IL-17A feem ntau yog pro-inflammatory, thiab lawv raug suav tias yog txuam nrog ntau yam kab mob autoimmune, suav nrog psoriasis, ankylosing spondylitis (AS), rheumatoid mob caj dab (RA), systemic lupus erythematosus (SLE) , and inflammatory bowel disease (IBD) [40].

Hauv psoriasis, pathogenicinflamation tau txhawb nqa los ntawm dysregulated IL-17 signaling. T17 hlwb tuaj yeem nkag mus rau ntawm daim tawv nqaij psoriatic, thiab inhibition ntawm IL-17A yog ib qho kev kho mob zoo rau psoriasis [41].

Hauv AS, T17 hlwb thiab IL-17A contributeto pathogenic o, thiab nws muaj txiaj ntsig zoo rau kev siv tshuaj tiv thaiv IL-17A monoclonal antibody los kho AS [42].Hauv cov neeg mob RA, IL{{5 }}A muaj nyob rau ntawm qhov chaw ntawm kev mob caj dab, thiab ntau dua ntawm IL-17+CD4+ T hlwb tau pom nyob rau hauv cov ntshav peripheral, tab sis qhov ua tau zoo ntawm brodalumab, tib neeg los tiv thaiv IL-17 Ib qho tshuaj tiv thaiv monoclonal, hauv kev kho mob ntawm RA yog qhov tsis zoo [40, 43,44].

Hauv cov neeg mob SLE, nce qib ntawm IL-23, IL-21, thiab IL-17 tau txheeb xyuas, uas cuam tshuam nrog kev nthuav dav ntawm T17 hlwb [40, 45]. Hauv cov neeg mob uas muaj IBD, qib siab ntawm IL-17 thiab IL-21 hauv cov ntshav tau qhia[40, 46].

Peb, lub luag hauj lwm ntawm T17 hlwb thiab IL-17A yog qhia nyob rau hauv lub pathogenesis ntawm CNS autoimmune mob. Ntau tus kab mob sclerosis (MS) yog kab mob CNS mob ntev, thiab tus qauv tsiaj feem ntau ntawm MS yog kev sim autoimmune encephalomyelitis (EAE), siv los tshawb txog cov kab mob ntawm MS. T17 hlwb yog ib qho ntawm cov tseem ceeb hauv MS thiab EAE, thiab MS tau raug cim tias feem ntau yog IL-17- kab mob sib kis autoimmune [47].

InMS cov neeg mob, kev qhia ntawm IL-17A thiab T17-cov ntaub ntawv sib txuas IL-6 tau nce hauv cov demyelinatedplaques [48], thiab cov noob qhia ntawm IL-17 qeb duas siab tshaj plaws nyob rau hauv CNS ntawm autopsy [48]. Te IL-17 qib inserum tau siab dua hauv cov neeg mob MS nrog kev rov qab los thiab kev tso tawm [49], nrog rau kev koom tes nrog cov kab mob ua haujlwm [50]. Qhov feem pua ​​​​ntawm T17 hlwb hauv cov ntshav tau nce ntxiv thaum lub sijhawm rov ua haujlwm [51, 52].

Hauv cov kua cerebral fluid (CSF), IL-17Ib theem tau nce siab hauv cov neeg mob rov qab los thiab tso tawm, nrog rau kev sib raug zoo rau qib ntawm cov ntshav-hlwb barrier (BBB) ​​tsis ua haujlwm [53].

Tus qauv EAE nas tau pom tias T17 hlwb tuaj yeem nkag mus rau lub hlwb [54] thiab IL-17 tuaj yeem cuam tshuam BBB [55]. Hauv cov qauv ntawm tes, T17 hlwb tau raug pov thawj los hla BBB, thiab qhov muaj T17 hlwb hauv cov kab mob ntawm CNS tau cuam tshuam rau kev txhim kho neuroinflamation [56].

T17 hlwb ua rau muaj kev cuam tshuam ntawm BBB [57], txhawb kev ua haujlwm ntawm astrocytes thiabmicroglia hauv CNS, thiab nthuav dav neuroinflammation hauv EAE los ntawm kev tsom mus rau cov neeg nyob hauv glial hlwb [58, 59].

Cov kev tshawb fawb tau pom tias IL-17 neutralization tuaj yeem txo qis EAE kev loj hlob los ntawm kev txo cov tiam ntawm cov kab mob cytokines [60], thiab EAE qhov hnyav tuaj yeem ua rau IL-17- cov nas tsis muaj zog [61–63]. Theem IIastudy ntawm secukinumab qhia tau hais tias ib qho IL-17A-neutralizing monoclonal antibody tej zaum yuav muaj txiaj ntsig zoo hauv kev txo qis kev ua haujlwm ntawm MRI hauv MS [64].

Th17 hlwb thiab IL-17A hauv cov kab mob neurodegenerative

Cov kab mob neurodegenerative yog tus cwj pwm los ntawm cov kev tsis zoo no ntawm qee cov hlwb neuronal, kev sib txawv ntawm cov protein sib xyaw, thiab cov tshuaj tiv thaiv kab mob tsis zoo[1].

Cov kev tshawb fawb tau pom tias IL-17Ib tug plays ib tug pathogenicrole nyob rau hauv ntau yam kab mob neurodegenerative [3].

Hais txog kev koom tes ntawm T17 hlwb thiab IL-17A nyob rau hauv Alzheimer'sdisease (AD), Parkinson's disease (PD), thiab amyotrophiclateral sclerosis (ALS), peb tau muab cov ntaub ntawv pov thawj thiab ntsuas cov ntaub ntawv muaj txiaj ntsig zoo, txhawm rau muab cov ntawv sau qhia kom meej. Cov txiaj ntsig tau txais txiaj ntsig ntawm lub hom phiaj T17/IL-17 los tsim kho tshiab rau cov neeg mob no (Fig. 1).

Tag nrho ntawm 146 tsab ntawv ceeb toom tau muab los ntawm cov ntsiab lus hauv qab no: "TH17", "IL-17", "Parkinson'sdisease", "PD", "Alzheimer's disease", "AD", "Amyotrophiclateral sclerosis", "ALS. ", "neurodegenerative kab mob".Thaum kawg, rau qhov kev tshawb fawb [65–70] ntawm kev kho mob rau IL-17 raug tshuaj xyuas (Table 1).

Th17 hlwb thiab IL-17A hauv AD

AD yog cov kab mob neurodegenerative uas tshwm sim ntau tshaj plaws, ua rau 70% ntawm tag nrho cov neeg mob dementia, thiab muaj kev nthuav dav zuj zus tom qab hnub nyoog 65 xyoos.

Pathologically, AD yog tus cwj pwm los ntawm kev tso tawm ntawm extracellular senile plaques tsim los ntawm amyloid- (A) thiab intracellular neurofibrillary tangles, uas tshwm sim los ntawm tsub zuj zuj ntawm hyperphosphorylated tau. Txog tam sim no, tseem tsis tau muaj qhov tseeb IL-17Kev hloov pauv hauv cov neeg mob AD.

Qee qhov kev tshawb fawb pom tias IL-17Ib qib hauv cov ntshav, lub hlwb, thiab CSF ntawm cov neeg mob AD tau nce, tab sis lwm cov kev tshawb fawb tau tshaj tawm txo IL-17Ib qib hauv cov neeg mob AD.

Cov txiaj ntsig tsis sib haum xeeb tuaj yeem yog vim tsis muaj qhov ntsuas kev kho mob tsis txaus ntseeg [71], tab sis tsis ntev los no meta-kev tshuaj ntsuam pom pom qhov tsis zoo ntawm cov kab mob kis ntawm AD thiab CSF IL-17A qib [72].

Txawm li cas los xij, cov kev tshawb fawb pom tau tias plasma IL-17 qib tuaj yeem siv los ua plasma biomarker kom paub qhov txawv ntawm cov neeg mob AD los ntawm cov neeg paub txog kev noj qab haus huv [73], thiab CSF IL-17 concentrations tuaj yeem siv los txheeb xyuas frontotemporal lobar degeneration (FTD) nrog tau pathology [74].

Ua kom T17 hlwb hauv CNS tuaj yeem tsim cov kab mob cytokines IL-17A, nrhiav cov neutrophils, ua kom cov kab mob inflammatory, thiab txhawb AD neuroinflammation thiab neurodegeneration [75, 76].

Cov kev hloov pauv caj ces raug suav tias yog tus neeg sib tw tseem ceeb los txhawb AD los ntawm kev tswj hwm ntawm IL-17A [77]. Cov pov thawj ntxiv tau pom tias IL-17 tau ua lub luag haujlwm hauv cov neuronal degeneration ntawm AD; Cov txheej txheem suav nrog Kev sib cuam tshuam, kev ua kom microglia, kev cuam tshuam BBB, kab mob neuroinflamation, thiab lwm yam. [77].

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