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IL-17A Softens the Skin: Antifibrotic Properties of IL-17A in Systemic Sclerosis

      IL-17A is abundant in scleroderma skin, but its pathologic role has remained unclear. In the Journal of Investigative Dermatology, Dufour et al. (2020) demonstrate a new role for IL-17A as an antifibrotic agent in scleroderma through modulation of keratinocyte responses to transforming growth factor-β and shifting of fibroblast responses from profibrotic to antifibrotic.

      Abbreviations:

      ECM (extracellular matrix), KCM (conditioned media from keratinocytes), MMP-1 (matrix metalloproteinase-1), SSc (systemic sclerosis), TGF-β (transforming growth factor-β)

       Introduction

      Systemic sclerosis (scleroderma, SSc) is a chronic debilitating autoimmune disease, characterized by marked fibrosis in the skin and internal organs and loss of adnexal structures in skin. SSc also features elevated inflammatory responses along with extensive microvascular damage (
      • Denton C.P.
      • Khanna D.
      Systemic sclerosis.
      ). The etiology of SSc is complex and still poorly understood, but multiple factors, including genetic predisposition and environmental stimuli, are thought to play a critical role. Multiple cell types have been implicated in its pathogenesis, including various immune cell subsets, fibroblasts and closely related myofibroblasts, vascular cells, and adipocytes. Recently, epithelial keratinocytes also have been proposed to contribute to SSc pathogenesis (
      • Takahashi T.
      • Asano Y.
      • Sugawara K.
      • Yamashita T.
      • Nakamura K.
      • Saigusa R.
      • et al.
      Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: possible roles in scleroderma.
      ). Furthermore, conditioned media from keratinocytes (KCM) obtained from patients with SSc, but not healthy controls, promote fibroblast activation (
      • McCoy S.S.
      • Reed T.J.
      • Berthier C.C.
      • Tsou P.S.
      • Liu J.
      • Gudjonsson J.E.
      • et al.
      Scleroderma keratinocytes promote fibroblast activation independent of transforming growth factor beta.
      ). Taken together, these reports suggest that SSc keratinocytes may have an active role in scleroderma pathogenesis through secretion of profibrotic factors.

       Keratinocyte-derived factors influence fibroblast production of collagen I

      • Dufour A.M.
      • Borowczyk-Michalowska J.
      • Alvarez M.
      • Truchetet M.-E.
      • Modarressi A.
      • Brembilla N.C.
      • Chizzolini C.
      IL-17A dissociates inflammation from fibrogenesis in systemic sclerosis.
      explored keratinocyte–fibroblast crosstalk to determine if keratinocyte-derived factors affect fibroblast function. To test this, the authors took KCM and added it to fibroblast cultures. They focused their analyses on two fibroblast-derived factors involved in extracellular matrix (ECM) turnover: collagen I, which is the main collagen seen in matrix deposition and fibrosis, and matrix metalloproteinase-1 (MMP-1), an enzyme (collagenase) that is involved in ECM breakdown. The authors examined the balance between the two, with increased levels of collagen I favoring matrix deposition and fibrosis and increased levels of MMP-1 favoring matrix degradation and antifibrotic response.
      Using this model, the authors found that KCM influences fibroblast function and favors matrix degradation over deposition. To characterize the factors involved, proteomic approaches were used to identify the keratinocyte-derived mediators in KCM. The most abundant proteins found in KCM were plasminogen activator inhibitor-1, thrombospondin-1, and platelet-derived growth factor. All of these have been reported previously to be dysregulated in scleroderma skin and shown to influence angiogenesis and fibrosis (
      • Lemaire R.
      • Burwell T.
      • Sun H.
      • Delaney T.
      • Bakken J.
      • Cheng L.
      • et al.
      Resolution of skin fibrosis by neutralization of the antifibrinolytic function of plasminogen activator inhibitor 1.
      ). Notably, inhibition of these mediators had no effect on collagen I or MMP-1 levels produced by fibroblasts, but inhibition of transforming growth factor-β (TGF-β) and IL-1, which were detected at low levels in KCM, affected collagen I and MMP-1 expression, respectively. Next, the authors compared the effect of KCM on fibroblasts derived from healthy donors and fibroblasts derived from patients with SSc. Interestingly, fibroblasts from patients with SSc produced higher levels of collagen I than healthy control fibroblasts but exhibited no change in MMP-1 levels, suggesting that SSc fibroblasts are primed toward matrix deposition and fibrotic responses. KCM from SSc-derived keratinocytes was not studied, but SSc KCM has been shown to promote fibrosis in a TGF-β independent manner (
      • McCoy S.S.
      • Reed T.J.
      • Berthier C.C.
      • Tsou P.S.
      • Liu J.
      • Gudjonsson J.E.
      • et al.
      Scleroderma keratinocytes promote fibroblast activation independent of transforming growth factor beta.
      ).

       IL-17A: profibrotic or antifibrotic?

      IL-17A has been shown to be increased in both the blood and skin of patients with SSc (
      • Kurasawa K.
      • Hirose K.
      • Sano H.
      • Endo H.
      • Shinkai H.
      • Nawata Y.
      • et al.
      Increased interleukin-17 production in patients with systemic sclerosis.
      ), and an IL-17A signature is correlated positively with transcriptome changes in the blood of patients with SSc (
      • Higgs B.W.
      • Zhu W.
      • Richman L.
      • Fiorentino D.F.
      • Greenberg S.A.
      • Jallal B.
      • et al.
      Identification of activated cytokine pathways in the blood of systemic lupus erythematosus, myositis, rheumatoid arthritis, and scleroderma patients.
      ). The role of IL-17A in the fibrotic response in SSc has been controversial. Most mouse models have pointed toward a profibrotic role of IL-17A. For example, in the bleomycin model of scleroderma, IL-17A has been found to increase fibroblast proliferation and collagen synthesis (
      • Yoshizaki A.
      • Yanaba K.
      • Iwata Y.
      • Komura K.
      • Ogawa A.
      • Akiyama Y.
      • et al.
      Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model.
      ), whereas IL-17A loss attenuates skin fibrosis in both the bleomycin and tight-skin models of SSc (
      • Okamoto Y.
      • Hasegawa M.
      • Matsushita T.
      • Hamaguchi Y.
      • Huu D.L.
      • Iwakura Y.
      • et al.
      Potential roles of interleukin-17A in the development of skin fibrosis in mice.
      ). One human study also supports a profibrotic role for IL-17 where the frequency of circulating T helper type 17 cells correlated with SSc activity, and supernatants from T helper type 17 cells induced collagen I production in an IL-17A–dependent manner (
      • Yang X.
      • Yang J.
      • Xing X.
      • Wan L.
      • Li M.
      Increased frequency of Th17 cells in systemic sclerosis is related to disease activity and collagen overproduction.
      ). In contrast, the remainder of human data point toward an antifibrotic role for IL-17A. Inverse correlations between IL-17A+ cell counts in skin and the extent of skin involvement has been observed (
      • Truchetet M.E.
      • Brembilla N.C.
      • Montanari E.
      • Lonati P.
      • Raschi E.
      • Zeni S.
      • et al.
      Interleukin-17A+ cell counts are increased in systemic sclerosis skin and their number is inversely correlated with the extent of skin involvement.
      ), and IL-17A has been shown to induce MMP-1 production by fibroblasts without having any effect on collagen I synthesis from either healthy or SSc fibroblasts (
      • Brembilla N.C.
      • Montanari E.
      • Truchetet M.E.
      • 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.
      ). Others have found that IL-17A suppresses collagen I expression in SSc fibroblasts (
      • Nakashima T.
      • Jinnin M.
      • Yamane K.
      • Honda N.
      • Kajihara I.
      • Makino T.
      • et al.
      Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts.
      ).
      As keratinocytes are thought to be the main targets of IL-17A, the authors set out to address whether IL-17A effects on keratinocytes (with or without TGF-β) would modulate signaling to healthy and SSc fibroblasts using both keratinocyte culture systems and organotypic full-thickness skin models. Using these two different models, the authors demonstrate that IL-17A has an antifibrotic response through induction of MMP-1. Notably, the authors show that this antifibrotic effect of IL-17A involves inhibition of TGF-β signaling and Wnt/β-catenin activation in fibroblasts.
      These data raise questions about other inflammatory skin diseases where IL-17A is increased, such as psoriasis where fibrosis is rarely if ever observed (
      • Martin D.A.
      • Towne J.E.
      • Kricorian G.
      • Klekotka P.
      • Gudjonsson J.E.
      • Krueger J.G.
      • et al.
      The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings.
      ). This would be in agreement with the findings presented here but would contradict the profibrotic role of IL-17A in murine models and at least one human study outlined above supporting a profibrotic role of IL-17A. It also raises the question of how to understand rare cases where psoriasis coexists with scleroderma; one report identifies improvement in both psoriasis and SSc skin tightening with the use of ustekinumab, an IL-12/IL-23 inhibitor that suppresses the IL-17A pathway in psoriatic skin (
      • Ichihara A.
      • Jinnin M.
      • Ihn H.
      Treatment of psoriasis with ustekinumab improved skin tightening in systemic sclerosis.
      ).
      The answers to these questions are unclear but are likely related to heterogeneity of the disease as well as the context of inflammation. SSc is a disease with marked heterogeneity in both clinical presentation and the molecular mechanisms that contribute to its pathogenesis. Not all cases of SSc carry a TGF-β–responsive signature (
      • Sargent J.L.
      • Milano A.
      • Bhattacharyya S.
      • Varga J.
      • Connolly M.K.
      • Chang H.Y.
      • et al.
      A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity.
      ). Furthermore, although TGF-β is thought to be one of the primary profibrotic cytokines, other cytokines and growth factors, including IL-13 and platelet-derived growth factor, are able to drive myofibroblast differentiation and fibroblast activation independent of TGF-β (
      • Deng X.
      • Jin K.
      • Li Y.
      • Gu W.
      • Liu M.
      • Zhou L.
      Platelet-derived growth factor and transforming growth factor beta 1 regulate ARDS-associated lung fibrosis through distinct signaling pathways.
      ,
      • Kaviratne M.
      • Hesse M.
      • Leusink M.
      • Cheever A.W.
      • Davies S.J.
      • McKerrow J.H.
      • et al.
      IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent.
      ,
      • McCoy S.S.
      • Reed T.J.
      • Berthier C.C.
      • Tsou P.S.
      • Liu J.
      • Gudjonsson J.E.
      • et al.
      Scleroderma keratinocytes promote fibroblast activation independent of transforming growth factor beta.
      ). This could be part of the explanation for the discrepancies observed with different models, particularly in vitro models that are reliant upon single agents (i.e., TGF-β) versus more complex in vivo murine models. This could explain the variable role of IL-17A in scleroderma, where the contexts of IL-17A and other cosecreted cytokines and growth factors such as TGF-β and the target cell populations (keratinocytes vs. direct fibroblast signaling) play a role. Therefore, further research into aggregate inflammatory responses is critical, as one cytokine may drive what sometimes appears to be completely opposite responses in different diseases or even different models of the same disease.
      In summary, the findings outlined by
      • Dufour A.M.
      • Borowczyk-Michalowska J.
      • Alvarez M.
      • Truchetet M.-E.
      • Modarressi A.
      • Brembilla N.C.
      • Chizzolini C.
      IL-17A dissociates inflammation from fibrogenesis in systemic sclerosis.
      provide novel insights into how IL-17A can shape different inflammatory diseases and can counteract profibrotic responses of TGF-β. How this can be utilized in the future for the benefit of patients with SSc remains to be seen, but exciting avenues for further studies can be envisioned.

      ORCIDs

      J. Michelle, Kahlenberg - https://orcid.org/0000-0002-4006-8945

      References

        • Brembilla N.C.
        • Montanari E.
        • Truchetet M.E.
        • 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
        • Deng X.
        • Jin K.
        • Li Y.
        • Gu W.
        • Liu M.
        • Zhou L.
        Platelet-derived growth factor and transforming growth factor beta 1 regulate ARDS-associated lung fibrosis through distinct signaling pathways.
        Cell Physiol Biochem. 2015; 36: 937-946
        • Denton C.P.
        • Khanna D.
        Systemic sclerosis.
        Lancet. 2017; 390: 1685-1699
        • Dufour A.M.
        • Borowczyk-Michalowska J.
        • Alvarez M.
        • Truchetet M.-E.
        • Modarressi A.
        • Brembilla N.C.
        • Chizzolini C.
        IL-17A dissociates inflammation from fibrogenesis in systemic sclerosis.
        J Invest Dermatol. 2020; 140: 103-112
        • Higgs B.W.
        • Zhu W.
        • Richman L.
        • Fiorentino D.F.
        • Greenberg S.A.
        • Jallal B.
        • et al.
        Identification of activated cytokine pathways in the blood of systemic lupus erythematosus, myositis, rheumatoid arthritis, and scleroderma patients.
        Int J Rheum Dis. 2012; 15: 25-35
        • Ichihara A.
        • Jinnin M.
        • Ihn H.
        Treatment of psoriasis with ustekinumab improved skin tightening in systemic sclerosis.
        Clin Exp Rheumatol. 2017; 35: 208-210
        • Kaviratne M.
        • Hesse M.
        • Leusink M.
        • Cheever A.W.
        • Davies S.J.
        • McKerrow J.H.
        • et al.
        IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent.
        J Immunol. 2004; 173: 4020-4029
        • Kurasawa K.
        • Hirose K.
        • Sano H.
        • Endo H.
        • Shinkai H.
        • Nawata Y.
        • et al.
        Increased interleukin-17 production in patients with systemic sclerosis.
        Arthritis Rheum. 2000; 43: 2455-2463
        • Lemaire R.
        • Burwell T.
        • Sun H.
        • Delaney T.
        • Bakken J.
        • Cheng L.
        • et al.
        Resolution of skin fibrosis by neutralization of the antifibrinolytic function of plasminogen activator inhibitor 1.
        Arthritis Rheumatol. 2016; 68: 473-483
        • Martin D.A.
        • Towne J.E.
        • Kricorian G.
        • Klekotka P.
        • Gudjonsson J.E.
        • Krueger J.G.
        • et al.
        The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings.
        J Invest Dermatol. 2013; 133: 17-26
        • McCoy S.S.
        • Reed T.J.
        • Berthier C.C.
        • Tsou P.S.
        • Liu J.
        • Gudjonsson J.E.
        • et al.
        Scleroderma keratinocytes promote fibroblast activation independent of transforming growth factor beta.
        Rheumatology (Oxford). 2017; 56: 1970-1981
        • Nakashima T.
        • Jinnin M.
        • Yamane K.
        • Honda N.
        • Kajihara I.
        • Makino T.
        • et al.
        Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts.
        J Immunol. 2012; 188: 3573-3583
        • Okamoto Y.
        • Hasegawa M.
        • Matsushita T.
        • Hamaguchi Y.
        • Huu D.L.
        • Iwakura Y.
        • et al.
        Potential roles of interleukin-17A in the development of skin fibrosis in mice.
        Arthritis Rheum. 2012; 64: 3726-3735
        • Sargent J.L.
        • Milano A.
        • Bhattacharyya S.
        • Varga J.
        • Connolly M.K.
        • Chang H.Y.
        • et al.
        A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity.
        J Invest Dermatol. 2010; 130: 694-705
        • Takahashi T.
        • Asano Y.
        • Sugawara K.
        • Yamashita T.
        • Nakamura K.
        • Saigusa R.
        • et al.
        Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: possible roles in scleroderma.
        J Exp Med. 2017; 214: 1129-1151
        • Truchetet M.E.
        • Brembilla N.C.
        • Montanari E.
        • Lonati P.
        • Raschi E.
        • Zeni S.
        • et al.
        Interleukin-17A+ cell counts are increased in systemic sclerosis skin and their number is inversely correlated with the extent of skin involvement.
        Arthritis Rheum. 2013; 65: 1347-1356
        • Yang X.
        • Yang J.
        • Xing X.
        • Wan L.
        • Li M.
        Increased frequency of Th17 cells in systemic sclerosis is related to disease activity and collagen overproduction.
        Arthritis Res Ther. 2014; 16: R4
        • Yoshizaki A.
        • Yanaba K.
        • Iwata Y.
        • Komura K.
        • Ogawa A.
        • Akiyama Y.
        • et al.
        Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model.
        J Immunol. 2010; 185: 2502-2515

      Linked Article

      • IL-17A Dissociates Inflammation from Fibrogenesis in Systemic Sclerosis
        Journal of Investigative DermatologyVol. 140Issue 1
        • Preview
          IL-17A is abundant in scleroderma but its role in fibrogenesis is controversial. We interrogated the role of IL-17A in extracellular matrix deposition and inflammation by investigating its effects on keratinocytes and fibroblasts cross-talk and in organotypic skin cultures. Keratinocyte-conditioned media of resting, IL-17A-, and/or transforming growth factor-β-primed primary keratinocytes were used to stimulate healthy donors and scleroderma fibroblasts. Alternatively, organotypic cultures of full human skin were challenged with these cytokines.
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