Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity

Giacomin, Paul R., Moy, Ryan H., Noti, Mario, Osborne, Lisa C., Siracusa, Mark C., Alenghat, Theresa, Liu, Bigang, McCorkell, Kelly A., Troy, Amy E., Rak, Gregory D., Hu, Yinling, May, Michael J., Ma, Hak-Ling, Fouser, Lynette A., Sonnenberg, Gregory F., and Artis, David (2015) Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity. The Journal of Experimental Medicine, 212 (10). pp. 1513-1528.

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Abstract

Innate lymphoid cells (ILCs) are critical for maintaining epithelial barrier integrity at mucosal surfaces; however, the tissue-specific factors that regulate ILC responses remain poorly characterized. Using mice with intestinal epithelial cell (IEC)-specific deletions in either inhibitor of κB kinase (IKK)α or IKKβ, two critical regulators of NFκB activation, we demonstrate that IEC-intrinsic IKKα expression selectively regulates group 3 ILC (ILC3)-dependent antibacterial immunity in the intestine. Although IKKβ(ΔIEC) mice efficiently controlled Citrobacter rodentium infection, IKKα(ΔIEC) mice exhibited severe intestinal inflammation, increased bacterial dissemination to peripheral organs, and increased host mortality. Consistent with weakened innate immunity to C. rodentium, IKKα(ΔIEC) mice displayed impaired IL-22 production by RORγt(+) ILC3s, and therapeutic delivery of rIL-22 or transfer of sort-purified IL-22-competent ILCs from control mice could protect IKKα(ΔIEC) mice from C. rodentium-induced morbidity. Defective ILC3 responses in IKKα(ΔIEC) mice were associated with overproduction of thymic stromal lymphopoietin (TSLP) by IECs, which negatively regulated IL-22 production by ILC3s and impaired innate immunity to C. rodentium. IEC-intrinsic IKKα expression was similarly critical for regulation of intestinal inflammation after chemically induced intestinal damage and colitis. Collectively, these data identify a previously unrecognized role for epithelial cell-intrinsic IKKα expression and TSLP in regulating ILC3 responses required to maintain intestinal barrier immunity.

Item ID: 40718
Item Type: Article (Research - C1)
ISSN: 1540-9538
Additional Information:

© 2015 Giacomin et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Funders: National Institutes of Health (NIH), USA, Burroughs Wellcome Fund, Crohn’s and Colitis Foundation of America, Australian National Health and Medical Research Council (NHMRC), Swiss National Science Foundation (SNSF), Cancer Research Institute
Date Deposited: 26 Oct 2015 03:38
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110707 Innate Immunity @ 50%
06 BIOLOGICAL SCIENCES > 0605 Microbiology > 060502 Infectious Agents @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 50%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 50%
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