Platelets Induce Thymic Stromal Lymphopoietin Production by Endothelial Cells: Contribution to Fibrosis in Human Systemic Sclerosis

Abstract

Taken together, these results identify HDMECs as contributors to TSLP production in SSc and suggest a potential mechanism by which platelets may profoundly affect the fibrotic process in SSc.

Editorial: Closing in on the Role of Thymic Stromal Lymphopoietin Inhibition as a Therapeutic Entry Point for Systemic Sclerosis

“…Truchetet et al confirm earlier observations of TSLP expression by epidermal epithelial cells and report increased numbers of TSLP‐secreting endothelial cells in the dermis of SSc patients as compared to healthy controls. The proportion of these TSLP‐expressing cells was strongly correlated with the modified Rodnan skin thickness score.…”

“…Previously, it was shown that keratinocytes in the skin of SSc patients and SSc‐like skin in mice triggered with bleomycin or poly(I‐C) (agonist of Toll‐like receptor 3 [TLR‐3]) produce high levels of TSLP . Associated with increased skin expression, systemic levels of TSLP in SSc patients were also strongly up‐regulated as compared to healthy controls . At present, it is unknown what drives TSLP expression in SSc skin keratinocytes, but innate signals, e.g., via TLRs and cytokines, including interferons (IFNs), IL‐13, and tumor necrosis factor (TNF) superfamily member LIGHT, have previously been demonstrated and could play a role in its induction in SSc .…”

“…As a steady circulating source of bioactive compounds, platelets contribute to the development of many characteristic phenomena of SSc, such as fibrosis and impaired vascular tone. In this issue of Arthritis & Rheumatology, Truchetet et al (1) describe a captivating novel mechanism of action by which platelets can contribute to immunopathology in SSc, namely, by interleukin-1b (IL-1b)/serotonin-dependent induction of thymic stromal lymphopoietin (TSLP) production by endothelial cells, substantiating the critical role of this cytokine in SSc (1).…”

The immunopathogenesis of fibrosis in systemic sclerosis

“…Mast cell A subset of SSc patients with localized scleroderma-like lesions were found to have an inflammatory phenotype leading to the activation of mast cells in the dermis of mechanically stressed skin [108] Dendritic cell After depletion of pDCs fibrosis was reverted in mice with established SSc-like disease. pDC depletion prior to induction of disease also prevented fibrosis [115] Platelets Activated platelets induced the production of the profibrotic mediator thymic stromal lymphopoietin (TSLP) in human dermal endothelial cells [128] Neutrophils Neutrophil activation was induced by SSc microparticles. Microparticles were derived from platelets and expressed the damage-associated molecular pattern HMGB1.…”

Early-Life Antibiotic Exposure Causes Intestinal Dysbiosis and Exacerbates Skin and Lung Pathology in Experimental Systemic Sclerosis

“…In our study, ATB exposure for different time periods significantly reduced diversity and abundance of bacterial species. TSLP is increased in the skin of patients with SSc, and implicated in microvasculopathy and fibrosis (Christmann et al, 2013;Truchetet et al, 2016;Usategui et al, 2013). Therefore, skin pathology in ATB-treated mice closely resembles SSc skin.…”