Garcinoic acid enhances inflammation resolution against colitis by activating Nrf2 dependent efferocytosis

Inflammation resolution represents the most crucial step in the inflammatory response, and its disruption is associated with a variety of disorders. Clearance of apoptotic cells, namely efferocytosis, plays a pivotal role in this process by preventing the transition of apoptotic cell accumulation into necrosis and fibrosis. Garcinoic acid (GA), a plant metabolite and a postbiotics analogue of vitamin E, has been demonstrated to possess antiinflammatory activity, but mechanistic aspects of this effect remain poorly characterized. In this study, we explored the potential of GA in enhancing efferocytosis and inflammation resolution. In vitro findings using macrophages indicated that GA enhances efferocytosis through the involvement of MerTK, LRP-1, and TIM4, and specialized pro-resolving lipid mediators (SPMs), mainly lipoxin A4 and resolvin E1. As in vivo, GA reduced inflammatory and degenerative symptoms in a mouse model of dextran sodium sulfate (DSS)-induced colitis, which was associated with increased efferocytosis activity in colon. Mechanistically, Nrf2 silencing and HO-1 inhibition in macrophages reduced both efferocytosis and SPMs effects of GA, suggesting that the proresolving role of this metabolite may depend, at least partially, on Nrf2 activity and stress response effects. Present findings demonstrate a role of GA as efferocytosis enhancer and potential therapeutic agent in nonresolving diseases.