OTULIN protects the intestinal epithelium from apoptosis during inflammation and infection

Abstract

The intestinal epithelium is a single cell layer that is constantly renewed and acts as a physical barrier that separates intestinal microbiota from underlying tissues. In inflammatory bowel disease (IBD) in humans, as well as in experimental mouse models of IBD, this barrier is impaired, causing microbial infiltration and inflammation. Deficiency in OTU deubiquitinase with linear linkage specificity (OTULIN) causes OTULIN-related autoinflammatory syndrome (ORAS), a severe inflammatory pathology affecting multiple organs including the intestine. We show that mice with intestinal epithelial cell (IEC)-specific OTULIN deficiency exhibit increased susceptibility to experimental colitis and are highly sensitive to TNF toxicity, due to excessive apoptosis of OTULIN deficient IECs. OTULIN deficiency also increases intestinal pathology in mice genetically engineered to secrete excess TNF, confirming that chronic exposure to TNF promotes epithelial cell death and inflammation in OTULIN deficient mice. Mechanistically we demonstrate that upon TNF stimulation, OTULIN deficiency impairs TNF receptor complex I formation and LUBAC recruitment, and promotes the formation of the cytosolic complex II inducing epithelial cell death. Finally, we show that OTULIN deficiency in IECs increases susceptibility to Salmonella infection, further confirming the importance of OTULIN for intestinal barrier integrity. Together, these results identify OTULIN as a major anti-apoptotic protein in the intestinal epithelium and provide mechanistic insights into how OTULIN deficiency drives gastrointestinal inflammation in ORAS patients.

Cell death as an architect of adult skin stem cell niches

“…autoinflammation and even carcinogenesis due to enhanced apoptotic and necroptotic responses in KCs [78,87]. This is not the case in other high-turnover SC niches, such as the intestinal epithelium, where OTULIN deficiency does not cause spontaneous pathology [90].…”

OTULIN haploinsufficiency predisposes to environmentally directed inflammation

“…While ORAS patients have not been documented with susceptibility to infection, OTULIN haploinsufficiency is dominated by a high inflammatory response after infectious external triggers (S. aureus in humans and LPS in mice). Interestingly, predisposition to additional infectious diseases with an increased susceptibility to Salmonella infection in mice harboring a specific Otulin defect in intestinal epithelial cells has also been recently reported (13). The contribution of environmental triggers to disease manifestation in the context of a given genetic defect demonstrated in other mouse models (23, 24).…”

“…However, dermal fibroblasts of an ORAS patient were shown to be sensitized to TNF-induced cell death, and an increase in apoptotic cells was observed in skin lesions of an ORAS patient (9). In addition, selective knock-out of OTULIN in mouse keratinocytes, liver parenchymal cells, or intestinal epithelial cells caused an inflammatory skin disorder (10), severe hepatitis with increased risk of hepatocellular carcinoma (12), or susceptibility to colitis (13) respectively. Finally, knock-in mice expressing catalytically inactive OTULIN died during midgestation due to defective Wnt signaling and excessive endothelial cell death (14).…”

OTULIN deficiency: focus on innate immune system impairment

“…This may disrupt the homeostasis of T cells, leading to autoimmune diseases. However, OTULIN deficiency in epithelial cells disrupts intestinal barrier integrity and exacerbates intestinal inflammation, contributing to the pathogenesis of inflammatory bowel disease in ORAS ( 48 ). Nevertheless, the molecular mechanism of these cell type-dependent differences remains elusive.…”