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John Henderson, Steven O’Reilly, A therapy for systemic sclerosis: STAT!, Rheumatology, Volume 57, Issue 10, October 2018, Pages 1695–1697, https://doi.org/10.1093/rheumatology/kex492
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This editorial refers to Role of STAT3 in skin fibrosis and transforming growth factor beta signalling, Mesias Pedroza et al., on pages 1838–50.
SSc is a rare autoimmune disorder associated with high morbidity and mortality, a consequence of the diffuse fibrosis that targets multiple organs as the disease progresses. Pathogenesis is thought to begin with an environmental insult triggering inflammation and the over-activation of fibroblasts, causing excessive and chronic extracellular matrix protein deposition—manifesting as fibrotic lesions. Skin fibrosis is the first visible symptom before the fibrosis spreads to internal organs, with lung dysfunction the most common cause of mortality.
Within the initial inflammation thought to drive fibrosis, the renowned pro-inflammatory cytokine IL-6 has been found to be elevated and to correlate with the skin thickening observed in patients [1]. A key regulator of many immune functions, IL-6 has been demonstrated to induce the differentiation of fibroblasts into pro-fibrotic myofibroblasts via so called trans-signalling, a mechanism dependent on the transcription factor signal transducer and activator of transcription 3 (STAT3) [2]. Most human cells (including fibroblasts) lack the cell surface IL-6 receptor (IL-6R) required for IL-6 binding. However, this is overcome by the release of a soluble IL-6R that can bind IL-6 and then subsequently the gp130 cell surface protein—allowing IL-6 to interact with a wider range of cells, that is, fibroblasts.
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