Enhancement of LC3-associated efferocytosis for the alleviation of intestinal inflammation

Abstract

LC3-associated phagocytosis (LAP) is an instrumental machinery for the clearance of extracellular particles including apoptotic cells for the alleviation of inflammation. While pharmacological approaches to modulate LAP for inflammation regulation have been poorly explored, in our study we identified a novel compound, columbamine (COL), which can trigger LAP and enhance efferocytosis in an animal model of colitis to attenuate inflammation. We found that COL directly binds to and biasedly activates FPR2 (formyl peptide receptor 2) to promote efferocytosis and alleviate colitis. Biochemically, COL induces an interaction between RAC1 and the PIK3C3/VPS34-RUBCN/RUBICON complex, stimulating LC3-associated efferocytosis. These findings provide a novel interpretation of the potential roles of LAP in regulating inflammatory bowel disease (IBD), reveal the relationship between G protein-coupled receptors (GPCRs) and LAP, and highlight the role of RAC1 in regulating the PIK3C3/VPS34-RUBCN complex in LAP.

Keywords: FPR2; IBD; LC3-associated phagocytosis; columbamine; efferocytosis.

Figure 1.

A diagram illustrating working machinery of columbamine (COL) on alleviation of colitis. COL binds to FPR2 and triggers FPR2 signaling, including stimulating cAMP response and RAC1 activity. RAC1 binds to the PIK3C3/VPS34-RUBCN complex for activating LAP and alleviating intestinal inflammation.