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STAT6 suppression prevents bleomycin-induced dermal fibrosis.
Huang, Jingjing; Puente, Hydia; Wareing, Nancy E; Wu, Minghua; Mayes, Maureen D; Karmouty-Quintana, Harry; Assassi, Shervin; Mills, Tingting W.
Afiliación
  • Huang J; Department of Geriatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • Puente H; Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • Wareing NE; Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • Wu M; Department of Internal Medicine, Division of Rheumatology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • Mayes MD; Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • Karmouty-Quintana H; Department of Internal Medicine, Division of Rheumatology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • Assassi S; Department of Internal Medicine, Division of Rheumatology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • Mills TW; Department of Internal Medicine, Division of Rheumatology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
FASEB J ; 37(2): e22761, 2023 02.
Article en En | MEDLINE | ID: mdl-36629780
Fibrosis of the skin and internal organs is a hallmark of systemic sclerosis (SSc). Although the pathogenesis of SSc is poorly understood, increasing evidence suggests that interleukins (IL)-4 and - 13 contribute to the pathogenesis of skin fibrosis by promoting collagen production and myofibroblast differentiation. Signal transducers and activators of transcription 6 (STAT6) is one of the most important downstream transcription factors activated by both IL-4 and IL-13. However, it is not completely understood whether STAT6 plays a role during the pathogenesis of skin fibrosis in SSc. In this study, we observed increased STAT6 phosphorylation in fibrotic skin samples collected from SSc patients as well as bleomycin-injected murine mice. Knockout of Stat6 in mice significantly (1) suppressed the expression of fibrotic cytokines including Il13, Il17, Il22, Ccl2, and the alternatively activated macrophage marker Cd206; (2) reduced the production of collagen and fibronectin, and (3) attenuated late-stage skin fibrosis and inflammation induced by bleomycin. Consistently, mice treated with STAT6 inhibitor AS1517499 also attenuated skin fibrosis on day 28. In addition, a co-culture experiment demonstrated that skin epithelial cells with STAT6 knockdown had reduced cytokine expression in response to IL-4/IL-13, and subsequently attenuated fibrotic protein expression in skin fibroblasts. On the other side, STAT6 depletion in skin fibroblasts attenuated IL-4/IL-13-induced cytokine and fibrotic marker expression, and reduced CXCL2 expression in co-cultured keratinocytes. In summary, our study highlighted an important yet not fully understood role of STAT6 in skin fibrosis by driving innate inflammation and differentiation of alternatively activated macrophages in response to injury.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerodermia Sistémica / Bleomicina Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esclerodermia Sistémica / Bleomicina Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: FASEB J Asunto de la revista: BIOLOGIA / FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos