Kev Kho Mob Tshiab Ntawm Fibrosis: Interleukin -33

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Ntu Ⅱ: Nuclear IL-33 txwv tsis pub hloov pauv thaum ntxov ntawm fibroblasts mus rau ib qho extracellular matrix-secreting phenotype

FrancescaGatti, Sobuj Mia, Clara Hammarström & et al.

Interleukin(IL)-33 yog cytokine uas zoo nkaus li kho kom haum xeebfibrosislos ntawm kev taw qhia los ntawm nws cov receptor ST2 (IL-33(Interleukin -33)R/L1RL1). Nws kuj yog, txawm li cas los xij, ib qho protein uas tom qab kev sib txuas tau txheeb xyuas rau lub cell nucleus, qhov twg nws zoo li cuam tshuam chromatin folding. Ntawm no peb piav qhia txog lub luag haujlwm tshiab rau nuclear IL-33(Interleukin -33)hauv kev tswj cov fibroblast phenotype hauv murine raumfibrosistsav los ntawm unilateral ureteral obstruction. Transcriptional profileing ntawm IL-33(Interleukin -33)-deficient ob lub raum 24h tom qab ligation qhia txhim kho kev nthuav qhia ntawm fibrogenic noob thiab enrichment ntawm gene teeb koom tes nyob rau hauv extracellular matrix tsim thiab remodeling. Cov kev hloov pauv no tso siab rau qhov cuam tshuam hauv lub cev ntawm IL-33(Interleukin -33)vim lawv tsis tau tsim dua los ntawm kev kho mob nrog cov tshuaj tiv thaiv kab mob nruab nrab rau IL-33(Interleukin -33)uas tiv thaiv IL-33R/ST2L receptor signaling los yog lawv tsis pom nyob rau hauv IL-33R/ST2- lub raum tsis txaus. Txhawm rau tshawb fawb ntxiv txog kev ua haujlwm hauv lub cev ntawm IL-33(Interleukin -33), peb tau tsim cov ntaub ntawv hloov pauv ntawm tib neeg fibroblasts, soj ntsuam qhov kev poob qis ntawm IL-33(Interleukin -33)skewed lub transcription profile los ntawm ib qho inflammatory mus rau ib tug myofibroblast phenotype, reflected nyob rau hauv ntau dua ntawm COL3A1. COL5A1and transgelin protein, nrog rau kev qhia qis qis ntawm IL6, CXCL8, CLL7 thiab CCL8.Nyob rau hauv xaus, peb qhov kev tshawb pom qhia tias nuclear IL-33(Interleukin -33)nyob rau hauv fibroblasts dampens cov lus teb thawj zaug profibrotic kom txog rau thaum cov stimuli tsis tu ncua, raws li kev tswj hwm los ntawm UUO, tuaj yeem hla qhov kev tiv thaiv no.

Kev kho tshiab ntawm fibrosis: Interleukin -33

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Txij li thaum nws tshawb pom, muaj kev cuam tshuam dav ntawm cov ntaub so ntswg-derived IL-33(Interleukin -33)tau pom nyob rau hauv cardiac hypertrophic remodeling, thiab nyob rau hauvfibrosisntawm lub ntsws, daim tawv nqaij, thiab daim siab 2. Cov teebmeem no yog txhua yam kho los ntawm kev sib cuam tshuam nrog nws cov cognate membrane-bound receptor ST2 (IL33R / IL1RL1). Tsis tshua muaj kev mloog tau them rau lub peev xwm ntawm qhov intranuclear cytokine no los hloov pauv hauv cov ntaub so ntswg-cov neeg nyob hauv stromal hlwb, thiab qhov ua haujlwm tseem ceeb ntawm nuclear IL-33(Interleukin -33)tseem tsis paub ². Ntawm no, peb ua ke kev tshuaj xyuas ntawm unilateral ureteral obstruction nyob rau hauv vivo nrog kev soj ntsuam ntawm tib neeg fibroblasts nyob rau hauv vitro los qhia lub luag hauj lwm tshiab rau nuclear IL-33(Interleukin -33)yog ib tug repressor ntawm interstitial cell-extracellular matrix deposition. Qhov kev txiav txim siab no tau los ntawm kev soj ntsuam tias cov lus teb pro-fibrotic thaum ntxov tau nthuav dav hauv IL-33(Interleukin -33)-cov nas tsis muaj peev xwm tab sis tsis yog los ntawm neutralizing IL-33(Interleukin -33)cov tshuaj tiv thaiv kab mob muab rau cov nas qus thiab saib xyuas qhov depletion ntawm IL-33(Interleukin -33)Nyob rau hauv tib neeg dermal fibroblasts augmented kev qhia ntawm extracellular matrix Cheebtsam thiab skewed activated fibroblasts rau ib tug prototypic myofibroblastic phenotype.

Nuclear localization ntawm IL-33(Interleukin -33)tau pom ob qho tib si nyob rau hauv cov hlwb nyob rau hauv lub raum interstitial qhov chaw uas raws li ib tug sequela rau ureteral obstructive mus rau hauv a-SMA ntxiv rau myofibroblasts thiab nyob rau hauv thawj tib neeg fibroblasts raug rau profibrotic stimuli. Ntxiv mus, qhov nce collagen transcription pom nyob rau hauv IL-33(Interleukin -33)-cov nas tsis muaj peev xwm pom tsis muaj nyob hauv cov nas qus uas tau muab nruab nrab IL-33(Interleukin -33)cov tshuaj tiv thaiv los yog hauv ST2-cov nas tsis muaj, qhia tias IL-33(Interleukin -33)dampens cov lus qhia ntawm extracellular matrix Cheebtsam los ntawm nws cov haujlwm nuclear. Yog li ntawd, peb hais tias IL -33(Interleukin -33)exerts active homeostatic nuclear functions nyob rau hauv fibroblasts uas tiv thaiv tus tswv tsev los ntawm unwarranted teb. Hauv qhov no, IL-33(Interleukin -33)induced los ntawm inflammatory ib puag ncig tej zaum yuav ua raws li ib tug natural suppressor ntawm profibrotic noob, zoo li yuav tsum tau ceev los ntawm lub xub ntiag ntawm pro-fibrotic cytokines zoo li TGF-. Cov qauv no sib raug zoo nrog cov kev soj ntsuam tsis ntev los no hais tias nuclear, tab sis tsis yog extracellular. IB -33(Interleukin -33) ua kom muaj txiaj ntsig zoo ntawm kev kho mob hauv cov nas, los ntawm kev ua kom NFkB kev ua haujlwm hauv keratinocytes thiab txwv kev mob ntau dhau.

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Thaum ntxov nce hauv collagens thiab extracellular matrix noob tsis txhais tau tias ncefibrosiskev txhim kho hauv UUO qauv. Ib qho kev piav qhia txog qhov tsis sib xws no tuaj yeem yog qhov tsis txaus ntseeg ua ntej thiab cov ntaub so ntswg puas tsuaj uas tshwm sim los ntawm kev ua tiav ureteral obstruction muaj zog txaus los hla lub homeostatic mechanism exerted los ntawm IL-33(Interleukin -33). Xav txog qhov tsis tuaj yeem hloov pauv ntawm UUO thiab nws qhov cuam tshuam rau lub raum ua haujlwm, qhov no tsis yog qhov xav tsis thoob. Ib qho yuav tsum xav txog tias kev ntxhov siab ntawm tes thiab kev puas tsuaj los ntawm UUO tom qab lub sijhawm cov ntsiab lus tuaj yeem kho qhov kev tso tawm ntawm IL-33(Interleukin -33)mus rau lub extracellular space713, txo nws cov tsub zuj zuj nyob rau hauv lub nucleus thiab, tej zaum tseem ceeb tshaj, ua kom pro-fibrotic signaling ntawm nws receptor ST2L. Tseeb, lub luag hauj lwm pro-fibrotic rau IL-33-ST2L signaling tau raug tshaj tawm nyob rau hauv ntau lub cev, nrog rau lub raum. Txawm li cas los xij, peb tsis tau pom ib qho pov thawj ntawm lub luag haujlwm pro-fibrotic rau IL-33(Interleukin -33)nyob rau hauv peb lub cev txawm nyob rau hauv kev siv zog los rov tsim dua qhov tseeb sim tej yam kev mob yav tas los siv los ua kom pom qhov tshwm sim no.

Cov lus qhia nuclear ntawm IL -33(Interleukin -33)nyob rau hauv fibroblasts yog induced los ntawm inflammatory activation8.19, thiab qhov txhab-kho thwmsim qhia tau hais tias qhov induction yog txuam nrog rau ib tug thaum ntxov ua kom lub xeev ntawm lub cell. Cov nyhuv ntawm nuclear IL-33(Interleukin -33)Yog li ntawd tsis zoo li yuav tsum tau exerted rau ntawm quiescent fibroblast, tab sis, theej nyob rau theem nrab ntawm actuation. Peb qhov kev soj ntsuam tias depletion ntawm IL-33(Interleukin -33)augmented cov lus qhia ntawm extracellular matrix Cheebtsam xws li COL5Al thiab TGLN, tab sis txo cov kev qhia ntawm proinflammatory cytokine IL6 thiab chemokines CXCL8, CCL7 thiab CCL8, qhia hais tias tus qauv qhia qhov txawv ntawm inflammatory (ILd-a-SMA) thiab myofibroblastic (IL6 degree "a. -SMA-2)fibroblastic phenotypes hauv pancreatic cancer2 tuaj yeem muaj feem cuam tshuam nrog thaum xav txog kev ua haujlwm nuclear ntawm IL-33(Interleukin -33)nyob rau hauv kab lis kev cai myofibroblasts. Tej yam tshwm sim ntawm cov ntaub so ntswg o yuav tsum tau khaws cia rau hauv siab thaum xav txog tag nrho cov txiaj ntsig ntawm IL-33(Interleukin -33)- deficiency raufibrosiskev loj hlob. Inflamation yog ib qho tseem ceeb tsav raufibrosis. thiab tsawg kawg hauv lub ntsws, fibroblast secretion ntawm inflammatory cytokines zoo li CCL8 pab txhawb rau fibrosis pathology. Yog li ntawd, ib tus neeg tuaj yeem tsis tuaj yeem xav tias qhov kev tsis ncaj ncees ntawm cov kab mob fibroblastic phenotype inhibits txoj kev loj hlob mus ntev.fibrosis.

Peb qhov kev tshawb pom los ntawm cov kab lis kev cai ntawm tes qhia tau hais tias, dhau sijhawm, hloov pauv tag nrho myofibroblasts tuaj yeem txo qis hauv IL -33(Interleukin -33). Txawm hais tias IL -33(Interleukin -33)yog downregulated nyob rau hauv fibroblast kab lis kev cai nrog ntev raug rau TGF-B. Cov txiaj ntsig ntawm IL-33- depletion tseem tshwm sim, feem ntau yuav yog vim muaj ntau dua ntawm kev sib txawv ntawm myofibroblasts hauv kab lis kev cai. Qhov kev soj ntsuam no kuj txhawb qhov kev xav tias qhov cuam tshuam ntawm IL-33(Interleukin -33)yog vim muaj kev hloov pauv ntawm phenotype hloov dua siab tshiab es tsis yog los ntawm kev sib cuam tshuam ncaj qha rau hauv cellular uas inhibit pro-fibrotic signaling.

Cov kev sim yav tom ntej yuav tsum tau tsim los tshawb xyuas qhov cuam tshuam ntawm nuclear IL-33(Interleukin -33)ua haujlwm hauv fibroblasts nyob rau hauv cov xwm txheej sib txawv thiab txheeb xyuas cov txheej txheem molecular cuam tshuam. Ib txoj hauv kev nthuav dav heev yuav yog daim duab qhia thaj chaw chromatin uas nyob hauv I-33 hauv kev qhib fibroblasts los ntawm chromatin immunoprecipitation ua raws li kev sib sib zog nqus sib sib zog nqus thiab txheeb xyuas cov neeg koom tes sib cuam tshuam los ntawm immunoprecipitation thiab huab hwm coj spectrometry. Lwm txoj hauv kev yuav yog ib leeg-cell transcriptional profiling. Hauv cov ntsiab lus no, nws kuj tsim nyog hais tias peb cov ntaub ntawv murine hauv vivo tau ntxiv los ntawm kev sim hauv vitro hauv tib neeg fibroblasts. Raws li cov kab lis kev cai tseem ceeb ntawm tib neeg lub raum tsis tau yooj yim rau peb, peb tau muab qhov tseem ceeb rau qhov kev xav tau nrawm dua qhov cuam tshuam rau lub cev ntawm kev txaus siab hauv kev xaiv los tshawb nrhiav thiab txuas ntxiv hauv vivo cov ntaub ntawv hauv cov qauv hauv vitro.

Peb qhov kev tshawb pom ua ke ua rau nws txaus siab los tawm tswv yim rau ib qho qauv uas cov ntaub so ntswg puas thaum ntxov ua rau mesenchymal/fibroblastic cells induces intermediate fibroblastic phenotype nrog kev qhia siab ntawm nuclear IL-33(Interleukin -33)thiab feem ntaumobnta. Thaum tsis muaj cov ntaub so ntswg puas lawm, qhov no nuclear IL-33(Interleukin -33)tuaj yeem ua haujlwm los tiv thaiv kev hloov pauv tag nrho mus rau ib qho kev tsim tawm ntawm cov khoom siv hluav taws xob, myofibroblastic phenotype, yog li tiv thaiv kev tsim caws pliav ntau dhau thiab khaws cia lub cev ua haujlwm, Txawm li cas los xij, yog tias qhov cuam tshuam tsis zoo, xws li hauv UUO, kev tiv thaiv kev ua haujlwm ntawm IL{{2} }(Interleukin -33)yog overridden, thiab IL-33(Interleukin -33)tej zaum txawm yuav zais los ntawm activated fibroblasts degree rau exert pro-fibrotic ua los ntawm kev ua kom ST2, Nyob rau hauv cov ntsiab lus no, ib tug pharmacological kev cuam tshuam rau lub hom phiaj ntawm extracellular IL-33(Interleukin -33)thiab yog li ntawd thaiv cov pro-inflammatory thiab pro-fibrotic teeb liab ntawm IL-33-ST2L axis, tej zaum yuav muaj txiaj ntsig zoo hauv kev kho mob inflammatory thiab fibrotic kab mob.

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Cov ntaub ntawv

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