Baicalein Alleviates Fibrosis and Inflammation in Scleroderma Through Regulating B Cell Abnormalities

Background Scleroderma (Systemic sclerosis, SSc) is an autoimmune disorder characterized by multisystem extensive fibrosis, vascular changes and immunological dysregulation. B cell abnormalities play an essential role in the fibrotic pathogenesis of scleroderma by promoting autoantibodies and cytokines release as well as modulating the inflammatory processes. Baicalein, a phenolic flavonoid derived from the Chinese herb Scutellaria baicalensis Georgi, has been used in the treatment of the pathological processes of various fibrotic and inflammatory diseases. Here, we aimed to investigate the effect of baicalein on the major pathological characteristics of SSc both in vitro and in vivo, including fibrosis, B cell abnormalities and inflammation. Methods The effect of baicalein on collagen accumulation and expression of fibrogenic markers in human dermal fibroblasts were analyzed. The antifibrotic features of baicalein and its mechanisms were investigated in the bleomycin (BLM)-induced dermal fibrosis mice model by histologic examination, hydroxyproline assay, enzyme-linked immunosorbent assay and flow cytometry. Results 5-120 µM baicalein significantly abrogated total collagen deposition, decreased soluble collagen secretion, and inhibited the expression of various fibrogenesis molecules, including collagen(COL)1A1, COL1A2, COL3A1, connective tissue growth factor (CTGF), fibronectin, transforming growth factor β1 (TGF-β1) and alpha-smooth muscle actin (α-SMA) in both TGF β1- and PDGF-induced human CCC-ESF-1 dermal fibroblasts. In BLM-induced dermal fibrosis mice model, 25-100 mg/kg baicalein markedly attenuated dermal thickness and collagen accumulation in dose-dependent manners. Baicalein reduced the proportion of B220+ B cells, while increased the percentage of CD27+ memory B cells in the spleen of BLM-induced mice. Consistent with reversing B cell abnormalities, baicalein treatment potently attenuated serum levels of cytokines(IL-1β, IL-2, IL-4, IL6, IL-17A, TNF-α), chemokines (MCP-1, MIP-1β) and autoantibodies (anti-Scl-70, anti-PM-Scl, anti-centromeres and anti-dsDNA). Conclusions Baicalein inhibits TGF-β1 and PDGF- mediated ECM accumulation in human dermal fibroblasts and alleviates the development of experimental dermal fibrosis by reversing B cell abnormalities, reducing autoantibody production and ameliorating inflammation. Baicalein may have the potential to be further developed as a therapeutic candidate against SSc.