Autophagy in Crohn's Disease: Converging on Dysfunctional Innate Immunity

Abstract

Crohn's disease (CD) is a chronic inflammatory bowel disease marked by relapsing, transmural intestinal inflammation driven by innate and adaptive immune responses. Autophagy is a multi-step process that plays a critical role in maintaining cellular homeostasis by degrading intracellular components, such as damaged organelles and invading bacteria. Dysregulation of autophagy in CD is revealed by the identification of several susceptibility genes, including ATG16L1, IRGM, NOD2, LRRK2, ULK1, ATG4, and TCF4, that are involved in autophagy. In this review, the role of altered autophagy in the mucosal innate immune response in the context of CD is discussed, with a specific focus on dendritic cells, macrophages, Paneth cells, and goblet cells. Selective autophagy, such as xenophagy, ERphagy, and mitophagy, that play crucial roles in maintaining intestinal homeostasis in these innate immune cells, are discussed. As our understanding of autophagy in CD pathogenesis evolves, the development of autophagy-targeted therapeutics may benefit subsets of patients harboring impaired autophagy.

Keywords: ATG16L1; Crohn’s disease; ER stress; IRGM; NOD2; genetic susceptibility; inflammatory bowel disease; innate immunity; mitochondria; mitophagy; xenophagy.

Figure 1

Autophagy pathway. (1) mTOR inhibits the initiation of autophagy, whereas stress (such as bacterial infection or reactive oxygen species) activates AMPK that promotes activation of the ULK1 complex leading to the formation of a phagophore. (2, 3) Formation of the Beclin 1 complex facilitates elongation of the phagophore and cargo engulfment into a fully formed autophagosome. (4, 5) Lysosomes containing digestive enzymes (proteases and hydrolases) fuse with the autophagosome where the cargo is degraded.

Figure 2

Functional alterations during autophagy impairment in cells mediating mucosal innate immunity. Known functional alterations associated with autophagy dysfunction in intestinal innate immune cells relevant to CD.