B Cell Depletion Inhibits Fibrosis via Suppression of Profibrotic Macrophage Differentiation in a Mouse Model of Systemic Sclerosis

Abstract

Objective We undertook this study to investigate the effect of B cell depletion on fibrosis in systemic sclerosis (SSc) and its mechanism of action. Methods Mice with bleomycin‐induced SSc (BLM‐SSc) were treated with anti‐CD20 antibody, and skin and lung fibrosis were histopathologically evaluated. T cells and macrophages were cocultured with B cells, and the effect of B cells on their differentiation was assessed by flow cytometry. We also cocultured B cells and monocytes from SSc patients and analyzed the correlation between fibrosis and profibrotic macrophage induction by B cells. Results B cell depletion inhibited fibrosis in mice with BLM‐SSc. B cells from mice with BLM‐SSc increased proinflammatory cytokine–producing T cells in coculture. In mice with BLM‐SSc, B cell depletion before BLM treatment (pre‐depletion) inhibited fibrosis more strongly than B cell depletion after BLM treatment (post‐depletion) (P < 0.01). However, the frequencies of proinflammatory T cells were lower in the post‐depletion group than in the pre‐depletion group. This discrepancy suggests that the effect of B cell depletion on fibrosis cannot be explained by its effect on T cell differentiation. On the other hand, profibrotic macrophages were markedly decreased in the pre‐depletion group compared to the post‐depletion group (P < 0.05). Furthermore, B cells from mice with BLM‐SSc increased profibrotic macrophage differentiation in coculture (P < 0.05). In SSc patients, the extent of profibrotic macrophage induction by B cells correlated with the severity of fibrosis (P < 0.0005). Conclusion These findings suggest that B cell depletion inhibits tissue fibrosis via suppression of profibrotic macrophage differentiation in mice with BLM‐SSc, providing a new rationale for B cell depletion therapy in SSc.

Systemic Sclerosis–Associated Interstitial Lung Disease: How to Incorporate Two Food and Drug Administration–Approved Therapies in Clinical Practice

“…Acute-phase reactants, and specifically IL-6, play an important role in the pathogenesis of SSc-ILD. IL-6 is produced by B cells, proinflammatory macrophages (M1 macrophages), and myofibroblasts (29,30). In vitro studies suggest that IL-6 can favor the expression of IL-4 and IL-13 receptors, with a subsequent increase in profibrotic M2 macrophage polarization (31).…”

Pathogenetic Aspects of Systemic Sclerosis: A View Through the Prism of B Cells

“…In a recent study, B cells were extracted from mice with bleomycin induced scleroderma and were co-cultured with macrophages; it was shown that macrophages were skewed towards a profibrotic phenotype. Similarly, B cells from humans with severe dcSSc and associated ILD promoted the expression of CD206 on co-cultured macrophages which indicates a profibrotic response ( 86 ).…”

Epigenetic regulation of B cells and its role in autoimmune pathogenesis

“…Activated B cells can affect tissue fibrosis through diverse effector mechanisms in SSc [ 205 ]. Notably, B-cell depletion inhibits tissue fibrosis by suppressing profibrotic macrophage differentiation in a mouse model of SSc, further supporting an important role of B cells in the pathogenesis of SSc [ 206 ]. In SSc patients, global histone H4 hyperacetylation and histone H3K9 hypomethylation are detected in B cells.…”