In this study, we investigate the role of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in autoimmune diseases. We focus on oxidative regulation at the interaction between antigen-presenting cells (APCs) and T cells, and consequent effect of ROS and RNS on type II collagen (CII)-induced arthritis (CIA) model in mice.
Results:
Mice deficient in ROS and peroxide, due to a mutation in Ncf1 gene, develop an exaggerated CIA and a stronger T cell response to CII. In contrast, nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was found to protect against CIA. The most pronounced protective effect was observed when L-NAME treatment started immediately after CII immunization. Ten days after immunization, the CII-reactive T cell-proliferative response was greater in Ncf1-mutant mice that were treated with L-NAME. T cells from L-NAME-treated mice, primed with CII, showed lower interleukin-2 secretion in response to CII in vitro. Moreover, inhibition of RNS production resulted in dysregulation of NOS1 (neuronal) expression in CII-reactive T cells.
Innovation and Conclusion:
The results support that deficiency of a paracrine factor as ROS and peroxide released by APC leads to pronounced activation of T cells and enhanced arthritis. An intrinsic factor might be RNS produced by NOS1, which likely enhanced T cell activation in an autocrine manner.
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References
1.
BäcklundJ, CarlsenS, HögerT, HolmB, FuggerL, KihlbergJ, BurkhardtH, and HolmdahlR. Predominant selection of T cells specific for the glycosylated collagen type II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis. Proc Natl Acad Sci U S A, 99: 9960–9965, 2002.
2.
BäcklundJ, LiC, JanssonE, CarlsenS, MerkyP, NandakumarK-S, HaagS, YtterbergJ, ZubarevRA, and HolmdahlR. C57BL/6 mice need MHC class II Aq to develop collagen-induced arthritis dependent on autoreactive T cells. Ann Rheum Dis, 72: 1225–1232, 2013.
3.
CorthayA, BäcklundJ, BroddefalkJ, MichaëlssonE, GoldschmidtTJ, KihlbergJ, and HolmdahlR. Epitope glycosylation plays a critical role for T cell recognition of type II collagen in collagen-induced arthritis. Eur J Immunol, 28: 2580–2590, 1998.
4.
CuzzocreaS, ChatterjeePK, MazzonE, McDonaldMC, DugoL, Di PaolaR, SerrainoI, BrittiD, CaputiAP, and ThiemermannC. Beneficial effects of GW274150, a novel, potent and selective inhibitor of iNOS activity, in a rodent model of collagen-induced arthritis. Eur J Pharmacol, 453: 119–129, 2002.
5.
García-OrtizA and SerradorJM. Nitric oxide signaling in T cell-mediated immunity. Trends Mol Med, 24: 412–427, 2018.
6.
GeldermanKA, HultqvistM, HolmbergJ, OlofssonP, and HolmdahlR. T cell surface redox levels determine T cell reactivity and arthritis susceptibility. Proc Natl Acad Sci U S A, 103: 12831–12836, 2006.
7.
GeldermanKA, HultqvistM, PizzollaA, ZhaoM, NandakumarKS, MattssonR, and HolmdahlR. Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. J Clin Invest, 117: 3020–3028, 2007.
8.
GordonS. Phagocytosis: an immunobiologic process. Immunity, 44: 463–475, 2016.
9.
HolmdahlR, AnderssonM, GoldschmidtTJ, GustafssonK, JanssonL, and MoJA. Type II collagen autoimmunity in animals and provocations leading to arthritis. Immunol Rev, 118: 193–232, 1990.
10.
HuangY-F, LoP-C, YenC-L, NigrovicPA, ChaoW-C, WangW-Z, HsuGC, TsaiY-S, and ShiehC-C. Redox regulation of pro-IL-1β processing may contribute to the increased severity of serum-induced arthritis in NOX2-deficient mice. Antioxid Redox Signal, 23: 973–984, 2015.
11.
HultqvistM, OlofssonP, HolmbergJ, BackstromBT, TordssonJ, and HolmdahlR. Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. Proc Natl Acad Sci U S A, 101: 12646–12651, 2004.
12.
HultqvistM, SareilaO, VilhardtF, NorinU, OlssonLM, OlofssonP, HellmanU, and HolmdahlR. Positioning of a polymorphic quantitative trait nucleotide in the Ncf1 gene controlling oxidative burst response and arthritis severity in rats. Antioxid Redox Signal, 14: 2373–2383, 2011.
13.
InglisJJ, CriadoG, MedghalchiM, AndrewsM, SandisonA, FeldmannM, and WilliamsRO. Collagen-induced arthritis in C57BL/6 mice is associated with a robust and sustained T-cell response to type II collagen. Arthritis Res Ther, 9: R113, 2007.
14.
Jourd'heuilD, Jourd'heuilFL, KutchukianPS, MusahRA, WinkDA, and GrishamMB. Reaction of superoxide and nitric oxide with peroxynitrite: implications for peroxynitrite-mediated oxidation reactions in vivo. J Biol Chem, 276: 28799–28805, 2001.
15.
KalyanaramanB, Darley-UsmarV, DaviesKJA, DenneryPA, FormanHJ, GrishamMB, MannGE, MooreK, RobertsLJ, and IschiropoulosH. Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic Biol Med, 52: 1–6, 2012.
16.
KelkkaT, KienhöferD, HoffmannM, LinjaM, WingK, SareilaO, HultqvistM, LaajalaE, ChenZ, VasconcelosJ, NevesE, GuedesM, MarquesL, KrönkeG, HelminenM, KainulainenL, OlofssonP, JalkanenS, LahesmaaR, Souto-CarneiroMM, and HolmdahlR. Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature. Antioxid Redox Signal, 21: 2231–2245, 2014.
LaubachVE, SheselyEG, SmithiesO, and ShermanPA. Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc Natl Acad Sci U S A, 92: 10688–10692, 1995.
19.
LeeS-W, ChoiH, EunS-Y, FukuyamaS, and CroftM. Nitric oxide modulates TGF-beta-directive signals to suppress Foxp3+ regulatory T cell differentiation and potentiate Th1 development. J Immunol Baltim Md 1950, 186: 6972–6980, 2011.
van LoosdregtJ, RossettiM, SpreaficoR, MoshrefM, OlmerM, WilliamsGW, KumarP, CopelandD, PischelK, LotzM, and AlbaniS. Increased autophagy in CD4 + T cells of rheumatoid arthritis patients results in T-cell hyperactivation and apoptosis resistance: Immunomodulation and immune therapies. Eur J Immunol, 46: 2862–2870, 2016.
22.
MillsCD, KincaidK, AltJM, HeilmanMJ, and HillAM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol, 164: 6166–6173, 2000.
23.
MoorePK, al-SwayehOA, ChongNW, EvansRA, and GibsonA. L-NG-nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilatation in vitro. Br J Pharmacol, 99: 408–412, 1990.
24.
NiedbalaW, BesnardA-G, JiangHR, Alves-FilhoJC, FukadaSY, NascimentoD, MitaniA, PushparajP, AlqahtaniMH, and LiewFY. Nitric oxide-induced regulatory T cells inhibit Th17 but not Th1 cell differentiation and function. J Immunol, 191: 164–170, 2013.
25.
NiedbalaW, CaiB, LiuH, PitmanN, ChangL, and LiewFY. Nitric oxide induces CD4+CD25+ Foxp3 regulatory T cells from CD4+CD25 T cells via p53, IL-2, and OX40. Proc Natl Acad Sci U S A, 104: 15478–15483, 2007.
26.
OlofssonP, HolmbergJ, TordssonJ, LuS, ÅkerströmB, and HolmdahlR. Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat Genet, 33: 25–32, 2003.
27.
OlssonLM, Johansson ÅC, GullstrandB, JönsenA, SaevarsdottirS, RönnblomL, LeonardD, WetteröJ, SjöwallC, SvenungssonE, GunnarssonI, BengtssonAA, and HolmdahlR. A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus. Ann Rheum Dis, 76: 1607–1613, 2017.
28.
OlssonLM, NerstedtA, LindqvistA-K, Johansson ÅCM, MedstrandP, OlofssonP, and HolmdahlR. Copy number variation of the gene NCF1 is associated with rheumatoid arthritis. Antioxid Redox Signal, 16: 71–78, 2012.
PizzollaA, GeldermanKA, HultqvistM, VestbergM, GustafssonK, MattssonR, and HolmdahlR. CD68-expressing cells can prime T cells and initiate autoimmune arthritis in the absence of reactive oxygen species. Eur J Immunol, 41: 403–412, 2011.
31.
PizzollaA, HultqvistM, NilsonB, GrimmMJ, EneljungT, JonssonI-M, VerdrenghM, KelkkaT, GjertssonI, SegalBH, and HolmdahlR. Reactive oxygen species produced by the NADPH oxidase 2 complex in monocytes protect mice from bacterial infections. J Immunol, 188: 5003–5011, 2012.
32.
RaposoB, MerkyP, LundqvistC, YamadaH, UrbonaviciuteV, NiaudetC, ViljanenJ, KihlbergJ, KyewskiB, EkwallO, HolmdahlR, and BäcklundJ. T cells specific for post-translational modifications escape intrathymic tolerance induction. Nat Commun, 9: 353, 2018.
33.
SakaguchiY, ShirahaseH, IchikawaA, KandaM, NozakiY, and UeharaY. Effects of selective iNOS inhibition on type II collagen-induced arthritis in mice. Life Sci, 75: 2257–2267, 2004.
34.
SarkarS, KorolchukVI, RennaM, ImarisioS, FlemingA, WilliamsA, Garcia-ArencibiaM, RoseC, LuoS, UnderwoodBR, KroemerG, O'KaneCJ, and RubinszteinDC. Complex inhibitory effects of nitric oxide on autophagy. Mol Cell, 43: 19–32, 2011.
35.
StuehrDJ and MarlettaMA. Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. Proc Natl Acad Sci U S A, 82: 7738–7742, 1985.
ValkoM, LeibfritzD, MoncolJ, CroninMTD, MazurM, and TelserJ. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol, 39: 44–84, 2007.
38.
VítečekJ, LojekA, ValacchiG, and KubalaL. Arginine-based inhibitors of nitric oxide synthase: therapeutic potential and challenges. Mediators Inflamm, 2012: 1–22, 2012.
39.
YangJ, ZhangR, LuG, ShenY, PengL, ZhuC, CuiM, WangW, ArnaboldiP, TangM, GuptaM, QiC-F, JayaramanP, ZhuH, JiangB, ChenS, HeJC, TingAT, ZhouM-M, KuchrooVK, MorseHC, OzatoK, SikoraAG, and XiongH. T cell–derived inducible nitric oxide synthase switches off T H 17 cell differentiation. J Exp Med, 210: 1447–1462, 2013.
40.
YangM, HaaseC, ViljanenJ, XuB, GeC, KihlbergJ, and HolmdahlR. Cutting Edge: processing of oxidized peptides in macrophages regulates T cell activation and development of autoimmune arthritis. J Immunol, 199: 3937–3942, 2017.
41.
ZhaoJ, MaJ, DengY, KellyJA, KimK, BangS-Y, LeeH-S, LiQ-Z, WakelandEK, QiuR, LiuM, GuoJ, LiZ, TanW, RasmussenA, LessardCJ, SivilsKL, HahnBH, GrossmanJM, KamenDL, GilkesonGS, BaeS-C, GaffneyPM, ShenN, and TsaoBP. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet, 49: 433–437, 2017.
42.
ZhongJ, OlssonLM, UrbonaviciuteV, YangM, BäckdahlL, and HolmdahlR. Association of NOX2 subunits genetic variants with autoimmune diseases. Free Radic Biol Med, 125: 72–80, 2018.
43.
ZhongJ, ScholzT, YauACY, GuerardS, HüffmeierU, BurkhardtH, and HolmdahlR. Mannan-induced Nos2 in macrophages enhances IL-17–driven psoriatic arthritis by innate lymphocytes. Sci Adv, 4: eaas9864, 2018.
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