Lub luag hauj lwm ntawm Cov Qauv Pom Zoo Receptors Thiab Microbiota hauv Neurological Disorders Part 2

Tus xov tooj zoo li receptors

TLRs yog ib tsev neeg uas tau hais tawm ntau heev ntawm transmembrane PRRs lub luag haujlwm rau kev pib xa cov teeb liab hauv qab teb rau PAMPs thiab cov ntaub so ntswg puas.

Transmembrane yog hais txog ib chav kawm ntawm cov proteins ntawm cov cell membrane uas tuaj yeem xa cov teeb liab tawm ntawm sab nraud mus rau hauv lub cell. Kev nco yog ib qho kev txawj ntse tshwj xeeb rau tib neeg. Nws tso cai rau peb khaws thiab ua cov ntaub ntawv tom qab tau txais nws kom peb thiaj li hloov tau zoo rau ib puag ncig.

Txawm hais tias peb tseem tsis tau nkag siab qhov tseeb ntawm kev sib raug zoo ntawm transmembrane thiab kev nco, ntau thiab ntau cov kev tshawb fawb tau pom tias yuav muaj qee qhov kev sib txuas ntawm transmembrane proteins thiab nco.

Transmembrane proteins yog dav faib nyob rau hauv lub hlwb, thiab lawv muaj peev xwm koom nyob rau hauv ntau yam kev lom neeg muaj feem xyuam rau kev nco. Piv txwv li, lawv tuaj yeem cuam tshuam ncaj qha lossis tsis ncaj qha cuam tshuam rau kev sib kis ntawm synapses, yog li cuam tshuam rau kev nco. Tsis tas li ntawd, lawv tuaj yeem tswj hwm kev loj hlob thiab ciaj sia ntawm cov paj hlwb thaum lub sij hawm neural txoj kev loj hlob, yog li cuam tshuam rau kev loj hlob ntawm kev nco.

Tsis tas li ntawd, qee qhov kev tshawb fawb kuj tau pom tias cov proteins transmembrane tuaj yeem cuam tshuam rau lub xeev kev ua haujlwm ntawm cov neurons thiab lawv cov lus teb rau sab nraud stimuli, yog li cuam tshuam rau peb lub peev xwm ua cov ntaub ntawv. Nyob rau hauv txoj kev no, transmembrane proteins tau dhau los ua cov molecules tseem ceeb rau kev tswj kev nco.

Tau kawg, peb tsis tuaj yeem xav tias cov proteins transmembrane yog txhua yam hais txog kev nco. Tib neeg lub cim xeeb raug cuam tshuam los ntawm ntau yam, xws li ib puag ncig, kev paub ntawm tus kheej, yam caj ces, thiab lwm yam. Txawm li cas los xij, nyob rau hauv txhua rooj plaub, transmembrane proteins yog ib qho tseem ceeb hauv kev tswj kev nco.

Hauv luv luv, txawm hais tias peb tseem tsis tau nkag siab qhov tseeb ntawm kev sib raug zoo ntawm transmembrane proteins thiab kev nco, muaj pov thawj ntxiv tias yuav muaj qee qhov kev sib txuas ntawm lawv. Yog li ntawd, hauv kev tshawb fawb yav tom ntej, peb tuaj yeem tsom mus rau kev sib raug zoo ntawm transmembrane proteins thiab kev nco qab los tshawb nrhiav qhov tsis paub ntawm tib neeg kev nco. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco zoo vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov zaub mov txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Localization ofeach TLR tso cai rau kev faib ua ob pawg, cov uas tau hais nyob rau hauv cov ntshav plasma (TLR1, TLR2, TLR4, TLR5, TLR6, TLR11) thiab cov uas qhia nyob rau hauv lub cytoplasm andorganelles (TLR3, TLR7, TLR8, TLR9) (Fig.

Txog niaj hnub no, 11 tib neeg thiab 13 nas TLRshave tau ua tus cwj pwm (Akira & Takeda, 2004). Kev ua kom muaj zog ntawm txhua TLR, tom qab kev paub tshwj xeebPAMP, ua rau muaj kev hloov pauv hauv cov receptor uas tso cai rau kev nrhiav neeg ua haujlwm ntawm qhov tsim nyog downstream signaling adaptor, tig mus ua kom cov transcriptionfactors tshwj xeeb, thiab cov lus teb hauv lub cev tsis muaj zog (Takeuchi & Akira, 2001).

Plaub lub adaptorproteins tau raug txheeb xyuas, txhua tus muaj lub luag haujlwm rau lub cev tiv thaiv kab mob. Piv txwv li, universal adapter protein MyD88 paub los ua kom muaj NF-κB thiab activator protein 1 (AP-1) ua rau kev qhia ntawm inflammatory cytokines xws li astumor necrosis factor- (TNF ).

Xwb, TLR3 thiab TLR4 tuaj yeem teeb liab los ntawm theadaptor protein Toll/IL-1 receptor domain-muaj adapter inducing interferon- (TRIF) los qhib hom-I interferon (IFN) (Fitzgerald li al. 2003).

Cov kev cai ntawm cov lus teb yog nruj tswj hwm los ntawm kev hloov kho tom qab kev txhais lus xws li glycosylation (Weber et al. 2004; Sun et al. 2006; Abdulkhalek et al. 2011; Iavarone et al. 2011) andubiquitination (Boone 0.2014; Boone et al. 2011). Ulevitch, 2004; Shembade et al. 2010; Guedeset al. 2014; Kinsella et al. 2018)

Kev cuam tshuam ntawm TLR activation lossis maturation tuaj yeem ua rau dysregulation ntawm cov tshuaj tiv thaiv kab mob (Barrat li al. 2005; Reynolds li al. 2010; Ziegler li al. 2011; SuarezFarinas et al. 2013; Cavalcante 2018 thiab al.

Txawm hais tias txuas mus ntxiv rau TLR ligands hauv plab lumen, IECs qhia txog qib qis ntawm TLRs. Kev taw qhia ntawm cov kab mob pathogenic ua rau muaj kev tswj hwm ntawm qee qhov TLRs, uas yog TLR2, TLR4, TLR5, thiab TLR9 (Muzio li al. 2000; Gewirtz li al. 2001; Ewaschuk et al. 2007), thaum lwm tus muaj cov kab mob sib txawv ntawm cov kab mob pathogenic.

TLRs ua lub luag haujlwm tseem ceeb hauv kev tswj hwm tus tswv-microbeinteractions thiab mucosal tiv thaiv kab mob hauv GI ib puag ncig.

Cov kev tshawb fawb tau tshwm sim qhia txog kev sib txuas tshiab ntawm TLRs thiab cov kab mob neurodegenerative, suav nrog AD, PD thiab MS. Ib qho kev sib txuas ntawm plab microbiota-associatedinflammation thiab lub hlwb amyloidosis hauv AD tau pom, nrog cov kab mob amyloids tuaj yeem pib qhov kev qhia ntawm inflammatory cytokines (Nishimori li al. 2012).

Hauv AD lub hlwb, pom muaj cov kab mob LPS ntau dua (Zhan li al. 2016), thiab kev tswj hwm ntawm LPS hauv cov nas ua rau lub sijhawm ntev ntawm amyloid- thiab kev txawj ntse tsis txaus (Kahn li al. 2012). Cov kev tshawb fawb ntxiv tau pom qhov nce hauv amyloid- hauv nas hlwb nrog rau kev hloov pauv hauv cov kab mob gutmicrobiota (Kaji et al. 2010).

LPS-dependent TLR4 signaling raug txo qis hauv AD nas, qhia tias TLR4 tuaj yeem ua lub luag haujlwm hauv kev tshwm sim kab mob (Go et al. 2016). Hauv PD cov neeg mob, misfolded -synuclein protein activates microglia ntawm TLR2, activating MyD88-dependentNF-κB signaling, nyob rau hauv lem nce qhov kev qhia ntawm TLRs. TLR4 kuj tseem muaj kev sib cuam tshuam nrog -synuclein thiab cov noob caj noob ces ntawm TLR4-cov nas tiv thaiv los ntawm neurodegeneration (Stefanova li al. 2011).

Kev ua kom lub plab permeability thiab cov kab mob sib kis tau ua rau TLR4 ua kom nyob rau hauv lub xub ntiag ntawm lub cortex tau pom nyob rau hauv cov nas nrog kev nyuaj siab (Martin-Hernandez li al. 2016). Thaum kawg, TLR2 qhia tau raug tswj hwm hauv ob tus neeg mob MS thiab, hauv tus qauv nas, kev sim autoimmuneencephalomyelitis (EAE) (Fujiwara li al. 2018).

Thaum cov kev taw qhia kev koom nrog tsis to taub zoo, TLR2 knock-out nas txhim kho EAE, qhia txog lub luag haujlwm rau TLR2 (Fujiwara li al. 2018). Cov kev tshawb fawb tau pom tias cov microbiota hauv MS cov neeg mob yog lub luag haujlwm ncaj qha rau kev tswj hwm ntawm TLR2 thiab nws lub luag haujlwm tom qab hauv kab mob (Wasko li al. 2020).

Ua ke, cov kev tshawb fawb no qhia txog qhov tseem ceeb ntawm TLR signaling nyob rau hauv txoj kev loj hlob ntawm ntau yam kab mob neurological thiab tam sim no tshiab kho cov tswv yim uas yuav kho tau lawv.Peb kev nkag siab txog cov kab mob neurological thiab qhov tseem ceeb ntawm lub plab microbiota nyob rau hauv lawv txoj kev loj hlob yog txuas mus ntxiv, nrog rau cov hom phiaj tshiab rau kev kho mob. raug txheeb xyuas.

PRRs tshwj xeeb tuaj yeem ua rau lub hom phiaj zoo nkauj vim lawv txoj haujlwm ua thawj kab ntawm kev tiv thaiv kab mob thiab lawv cov kev tswj tsis zoo hauv ntau cov kab mob pathologies (Mullen li al.2015).

Targeting ntawm TLR2 signaling los ntawm nce TLR2 kam rau ua nyob rau hauv tus qauv nas ntawm MSsignificantly enhanced CNS remyelination (Wasko li al. 2019). Kev poob ntawm kev ua haujlwm hloov pauv hauv TLR4 noob tau pom tias txhawm rau txhawm rau ua kom microglia thiab monocytes los ntawm Alzheimer's amyloid peptides hauv kev tshawb fawb hauv vitro (Walter li al. 2007).

Kev kho mob melatonin tau txais txiaj ntsig zoo hauv kev ua kom NLRP3 inflammasome ua rau tom qab LPS-induceddepressive-zoo li tus cwj pwm, nyob rau hauv ib feem ntawm kev txo microglia activation (Arioz li al. 2019). Cov kev tshawb fawb ntxiv ntawm cov txheej txheem no PRRs tswj yog xav tau los txheeb xyuas ntau lub hom phiaj hauv kev kho mob thiab tiv thaiv ntau yam. neurodegenerative thiab neurodevelopmental teeb meem.

PRRs nyob rau hauv lwm yam kab mob

Raws li lawv lub luag haujlwm hauv cov kab mob hauv lub paj hlwb, PRRs tau cuam tshuam rau kev txhim kho ntawm lwm yam kab mob, nrog rau cov kab mob autoimmune. Polymorphisms ntawm Nod1 thiab Nod2 tau cuam tshuam nrog kev ua rau muaj kev cuam tshuam ntau ntxiv rau Guillain-Barresyndrome, ib qho kab mob autoimmune uas tawm tsam lub paj hlwb peripheral (Kharwar etal. 2016).

Tsis tas li ntawd, kev nthuav qhia ntau ntxiv ntawm Nod1 thiab Nod2 tau raug sau tseg nyob rau hauv lub pathogenesis ntawm Vogt-Koyanagi-Harada syndrome, uas tsis tshua muaj autoimmune tsis meej (Deng li al.2016). Tsis tas li ntawd, polymorphisms hauv tsev neeg NLR ua rau muaj kev pheej hmoo ntawm kev tsim IBD, nrog rau Nod1 thiab Nod2 cov nas tsis muaj qhov ua rau pom qhov nce ntawm DSS-induced colitis severity (Natividad li al. 2012) thiab Nod2 mutations correlating dysbiosis hauv IBD cov neeg mob (Aschardet. 2019).

Ib qho nucleotide polymorphism (SNP) nyob rau ntawm chromosome 1q44 downstream ntawm NLRP3 yav dhau los tau cuam tshuam rau kev ua rau Crohn tus kab mob (CD) (Villani li al. 2009), tab sis cov kev tshawb fawb tsis ntev los no hauv Suav Han cov neeg mob (Zhang et al. 2014) thiab ib pawg ntawm cov neeg mob hauv tebchaws Askiv (Lewis et al. 2011) qhia tias SNPs hauv NLRP3 noob muaj feem cuam tshuam nrog cov kab mob ulcerative colitis (UC) dua li CD.

Txawm li cas los xij, qhov poob ntawm kev ua haujlwm CARD8 kev hloov pauv hauv cov neeg mob CD ua rau muaj kev ua kom NLRP3 nce ntxiv, qhia tias tej zaum yuav muaj lub luag haujlwm rau NRLP3 hauv CD pathogenesis (Schoultz li al. 2009; Mao et al. 2018). NLRP3−/− nas tau pom muaj siab dua tooxazolone-induced colitis, qhia txog lub luag haujlwm tiv thaiv kab mob inflammasome hauv UC (Itani etal. 2016).

Nyob rau hauv rooj plaub ntawm TLRs, receptor activation thiab tom qab NF-κB signaling nyob rau hauv lub plab yog qhov tseem ceeb rau kev ciaj sia ntawm enteric neurons lub luag hauj lwm rau lub plab motility. Knockout mousemodels qhia tias TLR4 yog ib qho tseem ceeb rau lub plab motility, nrog qeeb GI motility txuam nrog txo tus naj npawb ntawm nitrergic neurons (Anitha li al. 2012).

Cov kev tshawb fawb ua ntej qhia txog lub luag haujlwm rau TLR4 hauv kev txhim kho ntau yam kab mob atrophy (MSA), qhov twg, zoo ib yam li PD, MSA cov neeg mob tau pom tias muaj kev cuam tshuam cov protein sib txuas thiab kev nthuav qhia ntau dua ntawm TLR4 hauv lawv cov colonic sigmoid mucosa thaum piv rau kev noj qab haus huv (Engen et ib. 2017). Ua ke, cov kev tshawb pom no qhia txog lub luag haujlwm tseem ceeb ntawm NLRs ua si hauv ntau txoj hauv kev kab mob, qhia txog lawv lub peev xwm hauv kev tswj hwm lub cev.

Cov lus xaus

PRRs, tshwj xeeb tshaj yog cov tsev neeg NLR thiab TLR, tau cuam tshuam los ua cov teeb meem tshiab hauv kev txhim kho ntau yam kev puas siab puas ntsws, yuav ua rau muaj kev cuam tshuam nrog ntau lwm txoj hauv kev qhia.

Lawv cov qib siab ntawm kev qhia hauv ntau cov ntaub so ntswg, tshwj xeeb tshaj yog cov kab mob GI, ua rau lawv lub hom phiaj txaus nyiam rau kev kawm ntxiv ntawm gutmicrobiota thiab nws cov kev cuam tshuam rau tib neeg kev noj qab haus huv thiab kev loj hlob ntawm plab-hlwb hlwb.

Nyiaj txiag

Qhov kev tshawb fawb no tau txais kev txhawb nqa los ntawm NIH 1R01AT009365-01 (rau MGG).

Biography

Ciara Keogh tau txais nws BSc hauv Genetics (Hons) los ntawm Dublin City University hauv Dublin, Ireland hauv 2018. Thaum nws PhD ntawm University College Dublin, nyob rau hauv kev saib xyuas ntawm Dr. Eoin Cummins, nws tau ua haujlwm ntawm cov teebmeem ntawm carbon dioxide ntawm inflammatory signaling.

Shethen tau tsiv mus rau UC Davis, Tsev Kawm Ntawv ntawm Veterinary Medicine, qhov chaw uas nws kawm txog lub luag haujlwm ntawm cov tshuaj tua kab mob hauv microbiota-gut-brain axis signaling nyob rau hauv cov nas neonatal nyob rau hauv kev saib xyuas ntawm Dr Melanie Gareau.

Cov ntaub ntawv

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