Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic destructive joint disease. To date, the etiology and pathogenesis of RA have not been fully elucidated, but a large number of studies have indicated that hypoxia is an important feature of RA. Our study was designed to probe how hypoxia-induced exosome (exo) derived from synovial fibroblasts (SFs) affect RA. In this study, we found that hypoxic environment existed in synovial tissue of RA, and miR-424 expression was increased in RA, and exosome derived from synovial fibroblasts (SFs-exo) could significantly induce T cells differentiation, which Th17 cells increased and Treg cells decreased. Besides, SFs-exo affected the expression of related inflammatory cytokines. And, we also found that FOXP3 was a target gene of miR-424 and exo-miR-424 KD inhibited RA worsening. These results suggested that SFs-exo in hypoxia aggravates rheumatoid arthritis by regulating Treg/Th17 balance and thus may be a potential therapeutic target for RA.
Impact statement
A comparative study of osteoarthritis (OA) and RA mice was implemented to suggest that miR-424 expression was increased in RA, and exosome-miR-424 derived from synovial fibroblasts (SFs-exo) could significantly induce T cells differentiation in which Th17 cells increased and Treg cells decreased via targeting FOXP3. And thus, miR-424 may be a potential therapeutic target for RA.
MateenSShahzadSAhmadSNaeemSSKhalidSAkhtarKRizviWMoinS.Cinnamaldehyde and eugenol attenuates collagen induced arthritis via reduction of free radicals and pro-inflammatory cytokines. Phytomedicine2019;
53:70–8
2.
HelmickCGFelsonDTLawrenceRCGabrielSHirschRKwohCKLiangMHKremersHMMayesMDMerkelPAPillemerSRReveilleJDStoneJH.National arthritis data W. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum2008;
58:15–25
3.
HarrisonPPointonJJChapmanKRoddamAWordsworthBP.Interleukin-1 promoter region polymorphism role in rheumatoid arthritis: a meta-analysis of IL-1B-511A/G variant reveals association with rheumatoid arthritis. Rheumatology (Oxford)2008;
47:1768–70
4.
AletahaDSmolenJS.Diagnosis and management of rheumatoid arthritis: a review. JAMA2018;
320:1360–72
5.
YeXZhaoKWuCHuPFuH.Associations between genetic variants in immunoregulatory genes and risk of non-Hodgkin lymphoma in a Chinese population. Oncotarget2017;
8:10450–7
6.
StuartSMaherBHSutherlandHBentonMRodriguezALeaRAHauptLMGriffithsLR.Genetic variation in cytokine-related genes and migraine susceptibility. Twin Res Hum Genet2013;
16:1079–86
7.
LiuQTianJXuYLiCMengXFuF.Protective effect of RA on myocardial Infarction-Induced cardiac fibrosis via AT1R/p38 MAPK pathway signaling and modulation of the ACE2/ACE ratio. J Agric Food Chem2016;
64:6716–22
8.
KeenHIEmeryP.How should we manage early rheumatoid arthritis? From imaging to intervention. Curr Opin Rheumatol2005;
17:280–5
9.
ZhangRTianAWangJShenXQiGTangY.miR26a modulates Th17/T reg balance in the EAE model of multiple sclerosis by targeting IL6. Neuromol Med2015;
17:24–34
10.
LangrishCLChenYBlumenscheinWMMattsonJBashamBSedgwickJDMcClanahanTKasteleinRACuaDJ.IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med2005;
201:233–40
11.
HarringtonLEHattonRDManganPRTurnerHMurphyTLMurphyKMWeaverCT.Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol2005;
6:1123–32
12.
ParkHLiZYangXOChangSHNurievaRWangYHWangYHoodLZhuZTianQDongC.A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol2005;
6:1133–41
13.
BoissierMCAssierEBitonJDenysAFalgaroneGBessisN.Regulatory T cells (Treg) in rheumatoid arthritis. Joint Bone Spine2009;
76:10–4
14.
NiuQCaiBHuangZCShiYYWangLL.Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int2012;
32:2731–6
15.
TanLWuHLiuYZhaoMLiDLuQ.Recent advances of exosomes in immune modulation and autoimmune diseases. Autoimmunity2016;
49:357–65
16.
KowalJTkachMTheryC.Biogenesis and secretion of exosomes. Curr Opin Cell Biol2014;
29:116–25
17.
ThakurBKZhangHBeckerAMateiIHuangYCosta-SilvaBZhengYHoshinoABrazierHXiangJWilliamsCRodriguez-BarruecoRSilvaJMZhangWHearnSElementoOPaknejadNManova-TodorovaKWelteKBrombergJPeinadoHLydenD.Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res2014;
24:766–9
18.
ShaoHImHCastroCMBreakefieldXWeisslederRLeeH.New technologies for analysis of extracellular vesicles. Chem Rev2018;
118:1917–50
19.
SongJKimDHanJKimYLeeMJinEJ.PBMC and exosome-derived hotair is a critical regulator and potent marker for rheumatoid arthritis. Clin Exp Med2015;
15:121–6
20.
ZakeriZSalmaninejadAHosseiniNShahbakhshYFadaeeEShahrzadMKFadaeiS.MicroRNA and exosome: key players in rheumatoid arthritis. J Cell Biochem2019;
21.
AlexanderMHuRRuntschMCKageleDAMosbrugerTLTolmachovaTSeabraMCRoundJLWardDMO’ConnellRM.Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun2015;
6:7321
22.
NakasaTMiyakiSOkuboAHashimotoMNishidaKOchiMAsaharaH.Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum2008;
58:1284–92
FearonUCanavanMBinieckaMVealeDJ.Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nat Rev Rheumatol2016;
12:385–97
25.
Lund-OlesenK.Oxygen tension in synovial fluids. Arthritis Rheum1970;
13:769–76
26.
HuFMuRZhuJShiLLiYLiuXShaoWLiGLiMSuYCohenPLQiuXLiZ.Hypoxia and hypoxia-inducible factor-1alpha provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis. Ann Rheum Dis2014;
73:928–36
27.
BevaartLVervoordeldonkMJTakPP.Evaluation of therapeutic targets in animal models of arthritis: how does it relate to rheumatoid arthritis?Arthritis Rheum2010;
62:2192–205
28.
YangXZhaoYJiaXWangCWuYZhangLChangYWeiW.CP-25 combined with MTX/LEF ameliorates the progression of adjuvant-induced arthritis by the inhibition on GRK2 translocation. Biomed Pharmacother2019;
110:834–43
29.
XiaoHLasserCShelkeGVWangJRadingerMLunavatTRMalmhallCLinLHLiJLiLLotvallJ.Mast cell exosomes promote lung adenocarcinoma cell proliferation – role of KIT-stem cell factor signaling. Cell Commun Signal2014;
12:64
30.
HanLSongNHuXZhuAWeiXLiuJYuanSMaoWChenX.Inhibition of RELM-beta prevents hypoxia-induced overproliferation of human pulmonary artery smooth muscle cells by reversing PLC-mediated KCNK3 decline. Life Sci2020;
246:117419
31.
KinderlererARSteinbergRJohnsMHartenSKLidingtonEAHaskardDOMaxwellPHMasonJC.Statin-induced expression of CD59 on vascular endothelium in hypoxia: a potential mechanism for the anti-inflammatory actions of statins in rheumatoid arthritis. Arthritis Res Ther2006;
8:R130
32.
WarringtonKJTakemuraSGoronzyJJWeyandCC.CD4+, CD28-T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems. Arthritis Rheum2001;
44:13–20
33.
ZhouLChongMMLittmanDR.Plasticity of CD4+ T cell lineage differentiation. Immunity2009;
30:646–55
34.
AliSLeonardSAKukolyCAMetzgerWJWoolesWRMcGintyJFTanakaMSandrasagraANyceJW.Absorption, distribution, metabolism, and excretion of a respirable antisense oligonucleotide for asthma. Am J Respir Crit Care Med2001;
163:989–93
35.
FelekkisKTouvanaEStefanouCDeltasC.microRNAs: a newly described class of encoded molecules that play a role in health and disease. Hippokratia2010;
14:236–40
36.
LiPSpolskiRLiaoWLeonardWJ.Complex interactions of transcription factors in mediating cytokine biology in T cells. Immunol Rev2014;
261:141–56
37.
LuLFBoldinMPChaudhryALinLLTaganovKDHanadaTYoshimuraABaltimoreDRudenskyAY.Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell2010;
142:914–29
38.
HuffakerTBHuRRuntschMCBakeEChenXZhaoJRoundJLBaltimoreDO’ConnellRM.Epistasis between microRNAs 155 and 146a during T cell-mediated antitumor immunity. Cell Rep2012;
2:1697–709
39.
SawantDVWuHKaplanMHDentAL.The Bcl6 target gene microRNA-21 promotes Th2 differentiation by a T cell intrinsic pathway. Mol Immunol2013;
54:435–42
40.
RouasRFayyad-KazanHEl ZeinNLewallePRotheFSimionAAklHMourtadaMEl RifaiMBurnyARomeroPMartiatPBadranB.Human natural treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol2009;
39:1608–18
41.
ZhangSOuyangXJiangXGuDLinYKongSKXieW.Dysregulated serum MicroRNA expression profile and potential biomarkers in hepatitis C virus-infected patients. Int J Med Sci2015;
12:590–8
42.
KimJKangYKojimaYLighthouseJKHuXAldredMAMcLeanDLParkHComhairSAGreifDMErzurumSCChunHJ.An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med2013;
19:74–82
43.
SteinhilberJBoninMWalterMFendFBonzheimIQuintanilla-MartinezL.Next-generation sequencing identifies deregulation of microRNAs involved in both innate and adaptive immune response in ALK+ ALCL. PLoS One2015;
10:e0117780
44.
XuSTaoZHaiBLiangHShiYWangTSongWChenYOuYangJChenJKongFDongYJiangSWLiWWangPYuanZWanXWangCLiWZhangXChenK.miR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint. Nat Commun2016;
7:11406
45.
Di NunzioSCecconiMPasseriniLMcMurchyANBaronUTurbachovaIVignolaSValencicETommasiniAJunkerACazzolaGOlekSLevingsMKPerroniLRoncaroloMGBacchettaR.Wild-type FOXP3 is selectively active in CD4+CD25(hi) regulatory T cells of healthy female carriers of different FOXP3 mutations. Blood2009;
114:4138–41
46.
GodfreyVLWilkinsonJERussellLB.X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am J Pathol1991;
138:1379–87
47.
BennettCLChristieJRamsdellFBrunkowMEFergusonPJWhitesellLKellyTESaulsburyFTChancePFOchsHD.The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet2001;
27:20–1
48.
ZhengYChaudhryAKasAdeRoosPKimJMChuTTCorcoranLTreutingPKleinURudenskyAY.Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature2009;
458:351–6
49.
KochMATucker-HeardGPerdueNRKillebrewJRUrdahlKBCampbellDJ.The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol2009;
10:595–602
50.
ChaudhryARudraDTreutingPSamsteinRMLiangYKasARudenskyAY.CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science2009;
326:986–91
51.
GaoMLiuLXWuFLZhangXLiYYShiTLiDZHanTT.The Changes of Th17/Treg and related cytokines: IL-17, IL-23, IL-10, and TGF-beta in respiratory syncytial virus bronchiolitis rat model. Iran J Allergy Asthma Immunol2017;
16:386–95
52.
WakashinHHiroseKMaezawaYKagamiSSutoAWatanabeNSaitoYHatanoMTokuhisaTIwakuraYPuccettiPIwamotoINakajimaH.IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in mice. Am J Respir Crit Care Med2008;
178:1023–32
53.
KornTBettelliEOukkaMKuchrooVK.IL-17 and Th17 cells. Annu Rev Immunol2009;
27:485–517
54.
OhkuraNKitagawaYSakaguchiS.Development and maintenance of regulatory T cells. Immunity2013;
38:414–23
55.
ListonAGrayDH.Homeostatic control of regulatory T cell diversity. Nat Rev Immunol2014;
14:154–65
56.
SzekaneczZKochAE.Macrophages and their products in rheumatoid arthritis. Curr Opin Rheumatol2007;
19:289–95
57.
LiXTianFWangF.Rheumatoid arthritis-associated microRNA-155 targets SOCS1 and upregulates TNF-alpha and IL-1beta in PBMCs. Int J Mol Sci2013;
14:23910–21
58.
ZhengYSunLJiangTZhangDHeDNieH.TNFalpha promotes Th17 cell differentiation through IL-6 and IL-1beta produced by monocytes in rheumatoid arthritis. J Immunol Res2014;
2014:385352
59.
TianJChenJWGaoJSLiLXieX.Resveratrol inhibits TNF-alpha-induced IL-1beta, MMP-3 production in human rheumatoid arthritis fibroblast-like synoviocytes via modulation of PI3kinase/Akt pathway. Rheumatol Int2013;
33:1829–35
