Abstract

Background Restoring immune homeostasis is crucial for inflammation resolution, in which B cells play dual regulatory roles. A promising therapeutic strategy involves simultaneously suppressing proinflammatory B-cell activity while enhancing regulatory B cells (Bregs). Natural anti-inflammatory compounds, such as the flavonoid apigenin (API), may achieve this dual immunomodulation, yet the precise mechanisms of API on B cells remain incompletely understood.Purpose This study aimed to elucidate how API modulates B cells to exert immunoregulatory and protective effects in inflammatory conditions.Design In vitro B-cell functional and molecular assays were integrated with two mechanistically distinct in vivo models—collagen-induced arthritis (CIA) in DBA/1 mice and cecal ligation and puncture (CLP)–induced sepsis in C57BL/6 mice—to evaluate API’s dual immunomodulatory effects and therapeutic potential.Methods B cells from mouse splenocytes (n=5 per group) or human PBMCs (n=5 healthy donors) were assessed for differentiation, cytokine production, class switch recombination (CSR), and signaling pathways. p38 MAPK involvement was examined using pathway-specific inhibitors. In vivo, disease severity, survival, immune phenotypes, cytokines, and histopathology were evaluated.Results API increased IL-10⁺ Breg frequency by ~2-fold (P < 0.001) and reduced Aicda expression by ~60% (P < 0.001), while suppressing plasma cell differentiation via Prdm1 downregulation. These effects were p38 MAPK-dependent. In CIA mice, API reduced arthritis scores by ~45% (P < 0.01); in CLP-induced sepsis, 7-day survival improved from 0% to 70% (P < 0.05), with attenuated lung injury and pro-inflammatory cytokine levels. Collectively, API promotes immune homeostasis restoration in both chronic autoimmune and acute inflammatory settings.Conclusion API restores immune homeostasis in both chronic autoimmune and acute inflammatory settings by coordinating Breg differentiation and suppressing pathogenic