Targeting macrophage autophagy for inflammation resolution and tissue repair in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic, non-specific, recurrent inflammatory disease, majorly affecting the gastrointestinal tract. Due to its unclear pathogenesis, the current therapeutic strategy for IBD is focused on symptoms alleviation. Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis. Genome-wide association studies and subsequent functional studies have highlighted the critical role of autophagy in IBD via a number of mechanisms, including modulating macrophage function. Macrophages are the gatekeepers of intestinal immune homeostasis, especially involved in regulating inflammation remission and tissue repair. Interestingly, many autophagic proteins and IBD-related genes have been revealed to regulate macrophage function, suggesting that macrophage autophagy is a potentially important process implicated in IBD regulation. Here, we have summarized current understanding of macrophage autophagy function in pathogen and apoptotic cell clearance, inflammation remission and tissue repair regulation in IBD, and discuss how this knowledge can be used as a strategy for IBD treatment.

Keywords: Autophagy; Efferocytosis; Inflammation; Inflammatory bowel diseases; Macrophage; Tissue repair.

Figure 1

Strategies to enhance macrophage autophagy for the treatment of IBD. Macrophage autophagy at sites of inflammation in IBD can promote pathogen and apoptotic cell clearance, inflammation resolution and tissue repair. Firstly, macrophage autophagy promotes the recognition and phagocytosis of pathogens mediated by TLR, NLR and other macrophage surface receptors. Secondly, in addition to inhibiting the inflammatory response mediated by the NF-κB pathway, autophagy-related genes, such as ATG16L1, IRGM, GPR65, NPC1 and RNF186, are also involved in pathogen-containing phagosomes binding to lysosomes and degradation. Thirdly, Nrbf2 activates MON1–CCZ1–Rab7 to promote efferocytosis which induces the differentiation of macrophages into the anti-inflammatory M2 subtype. Fourthly, autophagy-activated macrophages secrete Wnt1, which promotes the repair of damaged epithelial barriers. Lyso lysosome, MDP muramyl dipeptide, AC apoptotic cells, TLR toll-like receptors, NLR NOD-like receptors, ROS reactive oxygen species, NPC Niemann-Pick type C