IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

STING-STAT6 Signaling Pathway Promotes IL-4+ and IFN-α+ Fibrotic T Cell Activation and Exacerbates Scleroderma in SKG Mice

  • Kun Hee Lee (Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea) ;
  • Jin Seok Woo (Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea) ;
  • Ha Yeon Jeong (Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea) ;
  • Jeong Won Choi (Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea) ;
  • Chul Hwan Bang (Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Jeehee Youn (Department of Anatomy & Cell Biology, College of Medicine, Hanyang University) ;
  • Sung-Hwan Park (Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Mi-La Cho (Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea)
  • Received : 2023.11.28
  • Accepted : 2024.09.25
  • Published : 2024.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Systemic sclerosis (SS) is an autoimmune disease and pathological mechanisms of SS are unclear. In this study, we investigated the role of T cells in the progression of SS using SKG mice and humanized mice. SKG mice have a spontaneous point mutation in ZAP70. We induced scleroderma in SKG mice and a humanized SS mouse model to assess whether T cell-mediated immune responses induce SS. As a result, we found increased dermal thickness, fibrosis, and lymphocyte infiltration in skin tissue in SKG SS mice compared to BALB/c mice (control). Also, blood cytokine level, including IL-4- and IFN-α which are produced by CD4+ T cells via STIM1/STING/STAT6/IRF3 signaling pathways, were increased in SKG mice. Interestingly, skin fibrosis was reduced by inhibiting STING pathway in skin fibroblast. Next, we demonstrated the pathophysiological role of IL-4 and IFN-α in skin fibrosis using a humanized SS mouse model and found increased IL-4- and IFN-α-producing CD4+ T cells and fibrosis. In this study, we found that STING-induced production of IL-4- and type I IFN by CD4+ T cells is a key factor in mouse model and humanized mouse model of SS. Our findings suggest that the STING/STAT6/IRF3 signaling pathways are potential therapeutic targets in SS.

Keywords

Acknowledgement

This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (RS-2023-00217274, Republic of Korea) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2022-KH127879[HV22C0069]).

References

  1. Boleto G, Allanore Y, Avouac J. Targeting costimulatory pathways in systemic sclerosis. Front Immunol 2018;9:2998.
  2. Castello-Cros R, Whitaker-Menezes D, Molchansky A, Purkins G, Soslowsky LJ, Beason DP, Sotgia F, Iozzo RV, Lisanti MP. Scleroderma-like properties of skin from caveolin-1-deficient mice: implications for new treatment strategies in patients with fibrosis and systemic sclerosis. Cell Cycle 2011;10:2140-2150.
  3. Almanzar G, Schmalzing M, Klein M, Hilligardt D, Morris P, Hofner K, Hajj NE, Kneitz H, Wild V, Rosenwald A, et al. Memory CD4+ T cells lacking expression of CCR7 promote pro-inflammatory cytokine production in patients with diffuse cutaneous systemic sclerosis. Eur J Dermatol 2019;29:468-476.
  4. Yamamoto T. Autoimmune mechanisms of scleroderma and a role of oxidative stress. Self Nonself 2011;2:4-10.
  5. Yap HY, Tee SZ, Wong MM, Chow SK, Peh SC, Teow SY. Pathogenic role of immune cells in rheumatoid arthritis: implications in clinical treatment and biomarker development. Cells 2018;7:161.
  6. Mavalia C, Scaletti C, Romagnani P, Carossino AM, Pignone A, Emmi L, Pupilli C, Pizzolo G, Maggi E, Romagnani S. Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis. Am J Pathol 1997;151:1751-1758.
  7. Radstake TR, van Bon L, Broen J, Hussiani A, Hesselstrand R, Wuttge DM, Deng Y, Simms R, Lubberts E, Lafyatis R. The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFbeta and IFNgamma distinguishes SSc phenotypes. PLoS One 2009;4:e5903.
  8. Xing X, Yang J, Yang X, Wei Y, Zhu L, Gao D, Li M. IL-17A induces endothelial inflammation in systemic sclerosis via the ERK signaling pathway. PLoS One 2013;8:e85032. 
  9. Brembilla NC, Montanari E, Truchetet ME, Raschi E, Meroni P, Chizzolini C. Th17 cells favor inflammatory responses while inhibiting type I collagen deposition by dermal fibroblasts: differential effects in healthy and systemic sclerosis fibroblasts. Arthritis Res Ther 2013;15:R151.
  10. Trebak M, Kinet JP. Calcium signalling in T cells. Nat Rev Immunol 2019;19:154-169.
  11. Woo JS, Srikanth S, Gwack Y. Modulation of Orai1 and STIM1 by cellular factors. In: Calcium Entry Channels in Non-Excitable Cells. Kozak JA, Putney JW Jr, edis. Boca Raton, FL; CRC Press/Taylor & Francis; 2018. p.73-92. 
  12. Srikanth S, Woo JS, Wu B, El-Sherbiny YM, Leung J, Chupradit K, Rice L, Seo GJ, Calmettes G, Ramakrishna C, et al. The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nat Immunol 2019;20:152-162.
  13. Son A, de Jesus AA, Schwartz DM. STIM1 holds a STING in its (N-terminal) tail. Cell Calcium 2019;80:192-193.
  14. Tanaka Y, Chen ZJ. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci Signal 2012;5:ra20.
  15. Zhang X, Shi H, Wu J, Zhang X, Sun L, Chen C, Chen ZJ. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol Cell 2013;51:226-235.
  16. Zhao B, Du F, Xu P, Shu C, Sankaran B, Bell SL, Liu M, Lei Y, Gao X, Fu X, et al. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. Nature 2019;569:718-722.
  17. Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, Du F, Ren J, Wu YT, Grishin NV, et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 2015;347:aaa2630.
  18. Chen H, Sun H, You F, Sun W, Zhou X, Chen L, Yang J, Wang Y, Tang H, Guan Y, et al. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell 2011;147:436-446.
  19. Santana-de Anda K, Gomez-Martin D, Monsivais-Urenda AE, Salgado-Bustamante M, GonzalezAmaro R, Alcocer-Varela J. Interferon regulatory factor 3 as key element of the interferon signature in plasmacytoid dendritic cells from systemic lupus erythematosus patients: novel genetic associations in the Mexican mestizo population. Clin Exp Immunol 2014;178:428-437.
  20. Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T, Akira S. Essential role of Stat6 in IL-4 signalling. Nature 1996;380:627-630.
  21. Hsu LY, Tan YX, Xiao Z, Malissen M, Weiss A. A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity. J Exp Med 2009;206:2527-2541.
  22. Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, Sakihama T, Matsutani T, Negishi I, Nakatsuru S, et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 2003;426:454-460.
  23. Hata H, Sakaguchi N, Yoshitomi H, Iwakura Y, Sekikawa K, Azuma Y, Kanai C, Moriizumi E, Nomura T, Nakamura T, et al. Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. J Clin Invest 2004;114:582-588.
  24. Park MJ, Park Y, Choi JW, Baek JA, Jeong HY, Na HS, Moon YM, Cho ML, Park SH. Establishment of a humanized animal model of systemic sclerosis in which T helper-17 cells from patients with systemic sclerosis infiltrate and cause fibrosis in the lungs and skin. Exp Mol Med 2022;54:1577-1585.
  25. Derk CT, Jimenez SA. Systemic sclerosis: current views of its pathogenesis. Autoimmun Rev 2003;2:181-191.
  26. Denton CP, Black CM. Scleroderma--clinical and pathological advances. Best Pract Res Clin Rheumatol 2004;18:271-290.
  27. O'Reilly S, Hugle T, van Laar JM. T cells in systemic sclerosis: a reappraisal. Rheumatology (Oxford) 2012;51:1540-1549.
  28. Famularo G, Procopio A, Giacomelli R, Danese C, Sacchetti S, Perego MA, Santoni A, Tonietti G. Soluble interleukin-2 receptor, interleukin-2 and interleukin-4 in sera and supernatants from patients with progressive systemic sclerosis. Clin Exp Immunol 1990;81:368-372.
  29. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 2004;4:583-594.
  30. Salmon-Ehr V, Serpier H, Nawrocki B, Gillery P, Clavel C, Kalis B, Birembaut P, Maquart FX. Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis. Arch Dermatol 1996;132:802-806. 
  31. Parel Y, Aurrand-Lions M, Scheja A, Dayer JM, Roosnek E, Chizzolini C. Presence of CD4+CD8+ double-positive T cells with very high interleukin-4 production potential in lesional skin of patients with systemic sclerosis. Arthritis Rheum 2007;56:3459-3467.
  32. Distler JH, Jungel A, Caretto D, Schulze-Horsel U, Kowal-Bielecka O, Gay RE, Michel BA, Muller-Ladner U, Kalden JR, Gay S, et al. Monocyte chemoattractant protein 1 released from glycosaminoglycans mediates its profibrotic effects in systemic sclerosis via the release of interleukin-4 from T cells. Arthritis Rheum 2006;54:214-225.
  33. Ong C, Wong C, Roberts CR, Teh HS, Jirik FR. Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur J Immunol 1998;28:2619-2629.
  34. Lee KS, Ro YJ, Ryoo YW, Kwon HJ, Song JY. Regulation of interleukin-4 on collagen gene expression by systemic sclerosis fibroblasts in culture. J Dermatol Sci 1996;12:110-117.
  35. Chizzolini C, Dufour AM, Brembilla NC. Is there a role for IL-17 in the pathogenesis of systemic sclerosis? Immunol Lett 2018;195:61-67.
  36. Kurasawa K, Hirose K, Sano H, Endo H, Shinkai H, Nawata Y, Takabayashi K, Iwamoto I. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 2000;43:2455-2463.
  37. Wilson MS, Madala SK, Ramalingam TR, Gochuico BR, Rosas IO, Cheever AW, Wynn TA. Bleomycin and IL-1beta-mediated pulmonary fibrosis is IL-17A dependent. J Exp Med 2010;207:535-552.
  38. Goncalves RS, Pereira MC, Dantas AT, Almeida AR, Marques CD, Rego MJ, Pitta IR, Duarte AL, Pitta MG. IL-17 and related cytokines involved in systemic sclerosis: Perspectives. Autoimmunity 2018;51:1-9.
  39. Simpson SR, Rego SL, Harvey SE, Liu M, Hemphill WO, Venkatadri R, Sharma R, Grayson JM, Perrino FW. T cells produce IFN-α in the TREX1 D18N model of lupus-like autoimmunity. J Immunol 2020;204:348-359.
  40. Ding X, Ren Y, He X. IFN-I mediates lupus nephritis from the beginning to renal fibrosis. Front Immunol 2021;12:676082.
  41. Skaug B, Assassi S. Type I interferon dysregulation in Systemic Sclerosis. Cytokine 2020;132:154635.
  42. Kippenberger S, Zoller N, Kleemann J, Muller J, Kaufmann R, Hofmann M, Bernd A, Meissner M, Valesky E. STAT6-dependent collagen synthesis in human fibroblasts is induced by bovine milk. PLoS One 2015;10:e0131783.
  43. Nguyen JK, Austin E, Huang A, Mamalis A, Jagdeo J. The IL-4/IL-13 axis in skin fibrosis and scarring: mechanistic concepts and therapeutic targets. Arch Dermatol Res 2020;312:81-92.