The Role Of Inflammation And Endoplasmic Reticulum Homeostasis In Health And Disease

A growing epidemic of obesity and inflammatory bowel disease is threatening the health of millions of people around the world. Recent studies have established that these diseases are associated with systemic chronic inflammation and/or disrupted endoplasmic reticulum (ER) homeostasis. However, the role of inflammation and ER homeostasis in health and disease is not well understood. In this dissertation, I elucidate the physiological role of inflammasome, TLR signaling and ER associated degradation in various metabolic diseases. First, I show (Sun et al. Diabetes 2012) that the onset of obesity associated hyperglycemia and hyperinsulinemia coincides with the activation of the inflammasome in white adipose tissue. But unexpectedly, the ATP-P2X7 signaling axis, a well-known inflammasome-activating pathway, does not mediate the inflammasome activation. The nature of the inflammasome-activating danger signal(s) in adipose tissue in obesity remains to be characterized. Second, we report (Ji and Sun et al. Cell Reports 2014) that chronic intake of a highfat diet (HFD), not a low-fat diet (LFD), leads to severe pulmonary damage and mortality in mice deficient in Toll-like receptors (TLR) 2 and 4 (DKO) in part via gut dysbiosis. This finding may be important for immunodeficient patients, particularly those on chemotherapy or radiotherapy, where gut microbiota-caused conditions are often life-threatening. i Third, we investigate (Sun and Shi et al. PNAS 2014) the physiological importance of the ER-associated degradation (ERAD) machinery, consisting of suppressor and/or enhancer of lin-12-like (Sel1L) and hydroxymethylglutaryl reductase degradation protein 1 (Hrd1). Hrd1 is a principle ER-resident E3 ligase and forms a complex with an adaptor protein Sel1L, responsible for the degradation of a subset of misfolded proteins in the ER. Using the inducible Sel1L knockout mouse and cell models, we provide the first in vivo evidence that Sel1L is indispensable for Hrd1 stability, ER homeostasis and survival. Fourth, we discover (Sun and Shi et al. 2014. Under review) that inositolrequiring enzyme 1[alpha] (IRE1[alpha]), the sensor of the unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. Enterocyte-specific Sel1Lknockout mice are more susceptible to experimental colitis, where IRE1[alpha] kinasemediated JNK activation contributes to epithelial inflammation. Interestingly, IRE1[alpha] degradation is conserved in humans, and SEL1L-HRD1 expression is greatly reduced in the inflamed gut of inflammatory bowel disease (IBD) patients. Hence, IRE1[alpha] degradation by Sel1L-Hrd1 ERAD is a key regulatory mechanism for IRE1[alpha] signaling and the maintenance of gut homeostasis. In conclusion, this dissertation provides key insights into the pathophysiological role of inflammation and ER homeostasis. Future studies based on this dissertation may provide new avenues and initial validation for intervention in human metabolic and intestinal diseases. i