Anemoside B4 alleviates DSS-induced colitis by inhibiting CD1d-dependent NLRP3 inflammasome activation in macrophages

Abnormal activation of the NLRP3 inflammasome in macrophages is closely associated with Ulcerative colitis (UC) and targeting the NLRP3 inflammasome has been proposed as a potential therapeutic approach, but the underlying mechanism by which it regulates intestinal inflammation remains unclear. Anemoside B4 (AB4) has anti-inflammatory activity, but whether it alleviates UC by inhibiting the activation of NLRP3 inflammasome remains unclear. More importantly, the molecular targets of AB4 remain unknown. Our study showed that AB4 had a strong anti-inflammatory effect dextran sodium sulfate (DSS)-induced colitis in WT mice, whereas the protective effects were lost in NLRP3 ^-/- mice. Interestingly, AB4 inhibited the activation of NLRP3 inflammasome in colonic macrophages without affecting intestinal epithelial cells. Mechanistically, AB4 might target CD1d thus reducing the AKT-STAT1-PRDX1-NF-κB signaling pathway, eventually inhibiting the activation of NLRP3 inflammasome. Macrophage-specific CD1d depletion had been shown to reverse the protective effect of AB4. Therefore, as a natural product with high safety index, AB4 might be considered a promising candidate drug for the treatment of colitis.