Autophagy: roles in intestinal mucosal homeostasis and inflammation

Abstract

The intestinal mucosa is a site of multiple stressors and forms the barrier between the internal and external environment. In the intestine, a complex interplay between the microbiota, epithelial barrier and the local immune system maintains homeostasis and promotes a healthy gut. One of the major cellular catabolic processes that regulate this homeostasis is autophagy. Autophagy is required to maintain anti-microbial defense, epithelial barrier integrity and mucosal immune response. Dysregulation of the autophagy process causes disruption of several aspects of the intestinal epithelium and the immune system that can lead to an inappropriate immune response and subsequent inflammation. Genome-wide association studies have found an association between several risk loci in autophagy genes and inflammatory bowel disease. The aim of the current review is to provide an update on the role of autophagy in intestinal mucosal physiology and in the control of inappropriate inflammation.

Keywords: Autophagy; Epithelium; Immune response; Inflammation; Intestinal mucosa; Microbiota.

Fig. 1

Mechanisms of macroautophagy. Stress signals activate AMPK and inhibits mTORC1. mTORC1 is inhibited by AMPK and activated by growth factor induced PI3K-Akt pathway that initiates autophagy. 1. Initiation: Activated AMPK and inhibited mTORC1 initiates ULK complex. 2. Nucleation: ULK complex recruits kinase complex to the PAS that results in the production of PI3P at the isolation membrane. 3. Elongation: PI3P recruits downstream Atg proteins for elongation of the membrane. Atg12–5 forms a complex with Atg16L1 that associates with isolation membrane. The Atg12–5-16 L1 complex along with Atg7 and Atg3 are required for the formation of LC3-II from LC3-I. The LC3-II mediates the elongation and completion of the autophagosome. 4. Fusion: Autophagosome fuses with the lysosome to form the autolysosome. Lysosomal enzymes degrade the contents of the autolysosome. In selective autophagy, adaptor proteins like p62 binds to ubiquitinated proteins and organelles, attaches them with LC3-II and brings them in the autophagosome for degradation

Fig. 2

Schematic representation of the role of normal autophagy in maintaining intestinal homeostasis. The intestinal mucosa includes several types of epithelial and immune cells. This schematic illustrates the importance and function of normal autophagy in the intestinal mucosa. Autophagy is critical in preventing the invasion and dissemination of pathogens (1) and maintaining barrier integrity (2). Autophagy regulates the secretion of AMPs from Paneth cells (3), the secretion of mucins from goblet cells (4) and the differentiation of EE cells in intestinal epithelial lining. Autophagy is involved in different immunological functions such as cytokine secretion (5), pathogen clearance by macrophages (6), antigen presentation by DCs (7), effector and memory T cell development (8), and secondary antibody response. The process of autophagy can regulate the interaction between the host and the gut microbiota (9). Autophagy also helps to maintain the balance between harmful and beneficial bacteria of the gut (10)

Fig. 3

Schematic representation of effect of impaired autophagy in intestinal mucosa. Defects in the autophagy system result in breakdown of mucosal homeostasis of the intestine. This diagram shows the state of the intestinal epithelium, mucosal immune system and microbiota in the context of impaired autophagy. Defective autophagy results in decreased AMP (1) and mucin (2) production, increased barrier permeability (3), increased bacterial invasion and dissemination (4), impaired cytokine production (5), reduced antigen presentation (6) and reduced T and B cell survival and development (7). Disrupted autophagy can alter the composition of bacteria within the gut, trending towards increased levels of pro-inflammatory species and decreased levels of anti-inflammatory species, thus, resulting in dysbiosis (8). Autophagy is required for the proper function of the gut and prevention of an exaggerated pro-inflammatory response