Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation

Abstract

Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage‐mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3‐associated phagocytosis (LAP), a non‐canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G‐protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL‐induced efferocytosis, anti‐colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3‐associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease.

Macrophage Perspectives in Liver Diseases: Programmed Death, Related Biomarkers, and Targeted Therapy

“…In addition, macrophage autophagy extends beyond the degradation of cellular components and encompasses a broader range of physiological mechanisms. These mechanisms include the cytosolic burial of damaged organelles, the prevention of oxidative stress, and the modulation of inflammatory cytokine production, particularly IL-1A and IL-1B [ 97 , 102 ]. Beyond its role in regulating liver diseases, macrophage autophagy has emerged as a promising therapeutic target for various inflammatory diseases such as colitis, atherosclerosis, and tuberculosis.…”