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Summary: The transcription repressor Bach2 plays a crucial role in shaping humoral immunity, but its cell-autonomous function remains elusive. Here, we reveal the mechanism by which Bach2 regulates effector cell maturation in peripheral B cells. In response to Toll-like receptor (TLR) agonists, Bach2 deficiency promotes the differentiation of follicular, but not marginal zone, B cells into effector cells, producing interleukin (IL)-6 and antibodies. This phenomenon is associated with changes in lipid metabolism, such as increases in CD36 expression, lipid influx, and fatty acid oxidation. Consistent with this, Bach2-deficient B cells exhibit elevated levels of mitochondrial oxidative stress, lipid peroxidation, and p38 activation. Mechanistically, Bach2 acts as a repressor of Cd36, and inhibition of CD36 or fatty acid oxidation reduces the differentiation of naive B cells into IL-6- and antibody-secreting cells. These results indicate Bach2 as a key metabolic checkpoint regulator crucial for maintaining a functionally quiescent state of follicular B cells.

Objective COVID-19 induces the development of autoimmune diseases, including SLE, which are characterised by inflammation, autoantibodies and thrombosis. However, the effects of COVID-19 on SLE remain unclear.Methods We investigated the effects of COVID-19 on SLE development and progression in three animal models. Plasmids encoding SARS-CoV-2 spike protein and ACE2 receptor were injected into R848-induced BALB/C lupus mice, R848-induced IL-1 receptor antagonist knockout (KO) lupus mice and MRL/lpr mice. Serum levels of albumin and autoantibodies, lymphocyte phenotypes and tissue histology were evaluated.Results In R848-induced BALB/C lupus mice, the SARS-CoV-2 spike protein increased autoantibody and albumin levels compared with vehicle and mock treatments. These mice also exhibited splenomegaly, which was further exacerbated by the spike protein. Flow cytometric analysis revealed elevated T helper 1 cell counts, and histological analysis indicated increased levels of the fibrosis marker protein α-smooth muscle actin. In KO mice, the spike protein induced splenomegaly, severe kidney damage and pronounced lung fibrosis. In the MRL/lpr group, spike protein increased the serum levels of autoantibodies, albumin and the thrombosis marker chemokine (C-X-C motif) ligand 4.Conclusion COVID-19 accelerated the development and progression of lupus by inducing autoantibody production, fibrosis and thrombosis.

Abstract Background MicroRNA (miRNA)-21-5p participates in various biological processes, including cancer and autoimmune diseases. However, its role in the development of fibrosis in the in vivo model of systemic sclerosis (SSc) has not been reported. This study investigated the effects of miRNA-21a-5p overexpression and inhibition on SSc fibrosis using a bleomycin-induced SSc mouse model. Methods A murine SSc model was induced by subcutaneously injecting 100 μg bleomycin dissolved in 0.9% NaCl into C57BL/6 mice daily for 5 weeks. On days 14, 21, and 28 from the start of bleomycin injection, 100 μg pre-miRNA-21a-5p or anti-miRNA-21a-5p in 1 mL saline was hydrodynamically injected into the mice. Fibrosis analysis was conducted in lung and skin tissues of SSc mice using hematoxylin and eosin as well as Masson’s trichrome staining. Immunohistochemistry was used to examine the expression of inflammatory cytokines, phosphorylated signal transducer and activator of transcription-3 (STAT3) at Y705 or S727, and phosphatase and tensin homologue deleted on chromosome-10 (PTEN) in skin tissues of SSc mice. Results MiRNA-21a-5p overexpression promoted lung fibrosis in bleomycin-induced SSc mice, inducing infiltration of cells expressing TNF-α, IL-1β, IL-6, or IL-17, along with STAT3 phosphorylated cells in the lesional skin. Conversely, anti-miRNA-21a-5p injection improved fibrosis in the lung and skin tissues of SSc mice, reducing the infiltration of cells secreting inflammatory cytokines in the skin tissue. In particular, it decreased STAT3-phosphorylated cell infiltration at Y705 and increased the infiltration of PTEN-expressing cells in the skin tissue of SSc mice. Conclusion MiRNA-21a-5p promotes fibrosis in an in vivo murine SSc model, suggesting that its inhibition may be a therapeutic strategy for improving fibrosis in SSc.