HOIL1 regulates group 3 innate lymphoid cell numbers in the colon and protects against systemic dissemination, colonic ulceration, and lethality fromCitrobacter rodentiuminfection

Abstract

AbstractHOIL1-deficient patients experience chronic intestinal inflammation and diarrhea as well as increased susceptibility to certain bacterial infections. HOIL1 is a component of the linear ubiquitin chain assembly complex (LUBAC) that regulates immune signaling pathways including NF-κB-activating pathways. We have shown previously that HOIL1 is essential for survival followingCitrobacter rodentiumgastrointestinal infection of mice, but the mechanism of protection by HOIL1 was not examined.C. rodentiumis a murine model for human attaching and effacing (A/E) pathogens, enteropathogenic and enterohemorrhagicEscherichia coli,that cause diarrhea and food-borne illnesses, and lead to severe disease in children and immunocompromised individuals. In this study, we found thatC. rodentiuminfection caused severe colitis and dissemination ofC. rodentiumto systemic organs inHoil1-/-mice. HOIL1 was important in radiation-resistant cells and in the innate immune response to limit early replication ofC. rodentiumin the intestine, and to modulate induction of inflammatory cytokines. Using cell type-specific knock-out mice, we found that HOIL1 was dispensable in intestinal epithelial cells (IEC), but was required in CD11c- and lysozyme 2-expressing myeloid cells to prevent weight loss and systemic dissemination ofC. rodentium. While HOIL1-deficiency did not affect populations of neutrophils or macrophages, dendritic cells and group 3 innate lymphoid cell (ILC3) numbers were reduced, resulting in a defect in IL-22 induction duringC. rodentiuminfection. Understanding the role HOIL1 plays in limiting the pathogenesis of A/E lesion-forming bacteria will provide further insights into the innate immune response to gastrointestinal pathogens and inflammatory disorders.