Mivebresib alleviates systemic lupus erythematosus-associated diffuse alveolar hemorrhage via inhibiting infiltration of monocytes and M1 polarization of macrophages

Abstract

BackgroundDiffuse alveolar hemorrhage (DAH) is a serious complication that can arise from systemic lupus erythematosus (SLE) and other autoimmune diseases. While current treatments for DAH have limitations and adverse side effects, recent evidence suggests that inflammatory macrophages play a crucial role in the development of DAH. In this study, we investigated Mivebresib, a BET protein-bromodomain-containing protein 4 (BRD4) inhibitor, as a potential treatment for DAH. ResultsOur findings show that Mivebresib effectively protected C57BL/6J mice against pristane-induced DAH by inhibiting the migration and polarization of monocytes and macrophages, as well as pathogenic B and T cells. Specifically, Mivebresib modified the distribution of leukocytes, impeded the polarization of inflammatory macrophages, and reduced the frequency of CD19 + CD5 + B cells in the lungs of pristane-treated mice. Furthermore, in vitro experiments demonstrated that Mivebresib inhibited LPS-induced M1 polarization of macrophages and the expression of pro-inflammatory cytokines, M1 marker genes, and chemokines-chemokine receptors while thwarting the secretion of IL-6 and TNF-α. Transcriptomic analysis suggested and experiments comfimed that Mivebresib inhibits M1 polarization via interrupting the p300/BRD4/HIF1A axis. ConclusionsOur study demonstrates that Mivebresib has therapeutic potential for the life-threatening complication of DAH caused by SLE. By inhibiting macrophage polarization and the infiltration of inflammatory cells, Mivebresib may offer a promising treatment option for patients suffering from this disease.