Cell type-specific role of autophagy against Citrobacter rodentium infectious colitis

Recently, genome-wide association studies linked some autophagy-related genes to increased inflammatory bowel disease susceptibility, which suggests that autophagy has an important role in the control of gut immunity. To examine the function of autophagy in different cell compartments in the intestine, we generated the Atg7, an essential gene for autophagy induction, conditional knockout mice in the intestinal epithelium (Atg7FL/FL;Villin-Cre mice). We injected mice with LPS and tested the inflammatory response in the intestine. Atg7FL/FL;Villin-Cre mice exhibited stronger activation of NF-κB and higher levels of TNF-α and IL-1β than WT mice. We also tested the autophagy function in fibroblasts NIH3T3 cells overexpressing mutant Atg4B, which have defect in autophagosome closure, and found that those cells showed enhanced NF-κB activation to LPS stimulation as well. These results suggest that autophagy deficiency in non-hematopoietic compartment can lead to excess inflammatory response against intestinal microorganisms. To confirm this point, we infected mice with C. rodentium and found that Atg7FL/FL;Villin-Cre mice showed aggravated histological intestinal injuries and higher TNF-α, IL-1β and IFN-γ levels in the colon than WT mice. Our findings suggest that autophagy in non-hematopoietic cells play an important role in the regulation of inflammation and host defense against C. rodentium. We are currently testing the function of Atg7 in the hematopoietic cell compartment.