Secukinumab and metformin ameliorate dermal fibrosis by decreasing tissue interleukin‐17 levels in bleomycin‐induced dermal fibrosis

Karataş, Ahmet; Çelik, Çiğdem; Öz, Burak; Akar, Zeynel Abidin; Etem, Ebru Önalan; Dağlı, Adile Ferda; Koca, Süleyman Serdar

doi:10.1111/1756-185x.14114

Cited by 11 publications

(12 citation statements)

References 50 publications

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“…Karatas et al. reported that secukinumab and metformin ameliorated dermal fibrosis in bleomycin-induced mouse models by decreasing dermal thickness and tissue IL-17A levels, suggesting the association of IL-17A with dermal fibrosis in animals ( 40 ). However the pro-fibrotic mechanisms of IL-17A in animal models cannot be applied to humans ( 1 ).…”

Section: Il-17 and Systemic Sclerosismentioning

confidence: 99%

“…One possible reason this anti-fibrogenic effect of IL-17A is not capable of containing the fibrosis in SSc could be that intrinsic differences between normal and SSc fibroblasts show that SSc fibroblasts are more resistant than their normal counterparts in response to collagen inhibition under the influence of IL-17. This property of SSc fibroblasts may help them escape or limit the anti-fibrotic effects of IL-17 ( 40 ).…”

Section: Il-17 and Systemic Sclerosismentioning

confidence: 99%

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The Yin and Yang of IL-17 in Systemic Sclerosis

2022

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IL-17 (IL-17A) is a pro-inflammatory cytokine produced by a sub-set of T helper cells termed Th17 cells primarily in response to cytokines like TGF-β and IL-23 and play an important role in host defense. IL-17 signals via the IL-17RA/RC heterodimer and the adaptor protein Act1 to activate both canonical and non-canonical pathways inducing transcriptional activation and stabilization of mRNAs. IL-17 appears to act not directly on immune cells but stimulates stromal cells such as endothelial and epithelial cells and fibroblasts to secrete other immunomodulatory factors. Fibroblast activated by IL-17 can support the growth and differentiation of immune cells. Studies have begun to uncover a dual role for IL-17; on one hand enhancing immune reactions and promoting inflammatory diseases and on the other decreasing responses and immune activity in established disease settings. The balance of double-edged sword effect of IL-17 and autoimmunity is illustrated in a variety of human diseases and experimental models of diseases. Specifically, the emerging interest in autoimmunity in systemic sclerosis (Scleroderma, SSc) has led to potential role of IL-17A as a target therapy in this disease.

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Section: Il-17 and Systemic Sclerosismentioning

confidence: 99%

Section: Il-17 and Systemic Sclerosismentioning

confidence: 99%

The Yin and Yang of IL-17 in Systemic Sclerosis

2022

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“…Therapeutic effects of metformin were also investigated in Sjögren’s syndrome [ 111 ], scleroderma [ 112 – 115 ], ankylosing spondylitis [ 116 ], and gout [ 117 ]. Metformin reversed salivary gland inflammation and hypofunction in murine Sjögren’s syndrome by controlling imbalanced T and B cell differentiation [ 111 ].…”

Section: Therapeutic Effects Of Metformin In Other Autoimmune Inflammatory Rheumatic Diseasesmentioning

confidence: 99%

“…Metformin reversed salivary gland inflammation and hypofunction in murine Sjögren’s syndrome by controlling imbalanced T and B cell differentiation [ 111 ]. To examine the effects of metformin on scleroderma, a mouse model of bleomycin-induced skin fibrosis was employed [ 112 – 115 ]. Metformin attenuated skin fibrosis in mice, as evidenced by reductions in skin thickness, collagen deposition, and numbers of myofibroblasts.…”

Section: Therapeutic Effects Of Metformin In Other Autoimmune Inflammatory Rheumatic Diseasesmentioning

confidence: 99%

Metformin and its therapeutic applications in autoimmune inflammatory rheumatic disease

Kim

Choe

Park

2022

Korean J Intern Med

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Metformin is a first-line therapeutic agent for type 2 diabetes. Apart from its glucose- lowering effect, metformin is attracting interest regarding possible therapeutic benefits in various other conditions. As metformin regulates cell metabolism, proliferation, growth, and autophagy, it may also modulate immune cell functions. Given that metformin acts on multiple intracellular signaling pathways, including adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation, and that AMPK and its downstream intracellular signaling control the activation and differentiation of T and B cells and inflammatory responses, metformin may exert immunomodulatory and anti- inflammatory effects. The efficacy of metformin has been investigated in preclinical and clinical studies on rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Sjögren’s syndrome, scleroderma, ankylosing spondylitis, and gout. In this review, we discuss the potential mechanisms through which metformin exerts its therapeutic effects in these diseases, focusing particularly on rheumatoid arthritis and osteoarthritis.

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“…Park, et al also reported on the efficacy of targeting IL-17 in bleomycin-induced mice and chronic graft-versus-host disease models ( 105 ). Using Secukinumab, a monoclonal antibody against IL-17A, Karatas, et al showed the amelioration of bleomycin-induced dermal fibrosis in mice ( 106 ). In humans, an active but not recruiting phase III trial of brodalumab (AMG 827), a human, anti-IL17 receptor monoclonal antibody, for SSc (Clinicaltrials.gov identifier: NCT03957681 ) is undergoing.…”

Section: Imbalance Of Treg Cells and Th17 Cells In Sscmentioning

confidence: 99%

The Pathophysiological Roles of Regulatory T Cells in the Early Phase of Systemic Sclerosis

et al. 2022

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Systemic sclerosis (SSc) is an autoimmune disease that is characterized by vascular damage and fibrosis. Both clinical manifestations and immunological disturbances are diverse according to the disease duration. Particularly, changes in immunological processes are prominent in the early phase of SSc. The orchestration of several subsets of immune cells promotes autoimmune responses and inflammation, and eventually stimulates pro-fibrotic processes. Many reports have indicated that CD4+ T cells play pivotal roles in pathogenesis in the early phase of SSc. In particular, the pathogenic roles of regulatory T (Treg) cells have been investigated. Although the results were controversial, recent reports suggested an increase of Treg cells in the early phase of SSc patients. Treg cells secrete transforming growth factor-β (TGF-β), which promotes myofibroblast activation and fibrosis. In addition, the dysfunction of Treg cells in the early phase of SSc was reported, which results in the development of autoimmunity and inflammation. Notably, Treg cells have the plasticity to convert to T-helper17 (Th17) cells under pro-inflammatory conditions. Th17 cells secrete IL-17A, which could also promote myofibroblast transformation and fibrosis and contributes to vasculopathy, although the issue is still controversial. Our recent transcriptomic comparison between the early and late phases of SSc revealed a clear difference of gene expression patterns only in Treg cells. The gene signature of an activated Treg cell subpopulation was expanded in the early phase of SSc and the oxidative phosphorylation pathway was enhanced, which can promote Th17 differentiation. And this result was accompanied by the increase in Th17 cells frequency. Therefore, an imbalance between Treg and Th17 cells could also have an important role in the pathogenesis of the early phase of SSc. In this review, we outlined the roles of Treg cells in the early phase of SSc, summarizing the data of both human and mouse models. The contributions of Treg cells to autoimmunity, vasculopathy, and fibrosis were revealed, based on the dysfunction and imbalance of Treg cells. We also referred to the potential development in treatment strategies in SSc.

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Secukinumab and metformin ameliorate dermal fibrosis by decreasing tissue interleukin‐17 levels in bleomycin‐induced dermal fibrosis

Cited by 11 publications

References 50 publications

The Yin and Yang of IL-17 in Systemic Sclerosis

The Yin and Yang of IL-17 in Systemic Sclerosis

Metformin and its therapeutic applications in autoimmune inflammatory rheumatic disease

The Pathophysiological Roles of Regulatory T Cells in the Early Phase of Systemic Sclerosis

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