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Regulation of Inflammation, Innate Immunity and Intestinal Homeostasis by HOIL1
Author(s) -
MacDuff Donna Alexandra,
Reese Tiffany A,
Baldridge Megan T,
Kimmey Jacqueline M,
Weiss Leslie A,
Song Christina,
Nice Timothy J,
Carrero Javier,
Colonna Marco,
Edelson Brian T,
Sibley David,
Stallings Christina L,
Casanova JeanLaurent,
Iwai Kazuhiro,
Virgin Skip
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.622.1
Subject(s) - immunology , innate immune system , inflammation , citrobacter rodentium , immunodeficiency , biology , immune system , inflammatory bowel disease , immunity , colitis , medicine , disease , pathology
The Linear Ubiquitin Chain Assembly Complex (LUBAC), composed of HOIL1, HOIP and SHARPIN, is an important regulator of NFκB activation in response to multiple stimuli. In humans, HOIL1 deficiency is associated with an immune disorder involving auto‐inflammation, immunodeficiency and inflammatory bowel disease (IBD)‐like symptoms. We found that barrier‐raised Hoil‐1 −/− mice are profoundly immunodeficient after acute infection with Listeria monocytogenes , Toxoplasma gondii or Citrobacter rodentium . Increased susceptibility to Listeria was due to a role for Hoil‐1 in hematopoietic cells and macrophages in production of protective cytokines. In contrast, Hoil‐1 −/− mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ‐herpesvirus 68 (MHV68), and these infections conferred a hyper‐inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of Hoil‐1 −/− and IL‐6 −/− mice in response to Listeria . Thus chronic herpesvirus infection generates signs of auto‐inflammation and effectively complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype‐phenotype studies. Furthermore, we found that susceptibility to enteric Citrobacter rodentium was due to a defect in innate immunity that resulted in spread of the bacteria to systemic sites early, and in ulceration of the distal colon late in the infection. However, induction of IL‐22, and other inflammatory cytokines in the distal colon, was not significantly impaired. Additionally, we found that Hoil1 −/− mice exhibited defective control of persistent enteric murine norovirus (MNV) infection, similar to interferon‐λ (IFNλ) receptor‐deficient mice, and Hoil1 was essential for the induction of IFNλ and IFNβ in bone marrow‐derived dendritic cells in response to MNV infection. Finally, we found that specific pathogen‐free Hoil1 −/− mice exhibited elevated Type 2 inflammatory cytokines in intestinal tissue, which drove morphological changes in intestinal epithelial cells in a STAT6‐dependent manner, and was partially ameliorated by antibiotics treatment. These data indicate that Hoil1 regulates inflammation and intestinal homeostasis in response to commensal microbes and enteric pathogens, and that HOIL1 disfunction may be an important contributor to inflammatory bowel disease pathology. Support or Funding Information Supported by the Crohn's and Colitis Foundation Genetics Initiative.