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

TitleEpithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity.
Publication TypeJournal Article
Year of Publication2015
AuthorsGiacomin, PR, Moy, RH, Noti, M, Osborne, LC, Siracusa, MC, Alenghat, T, Liu, B, McCorkell, KA, Troy, AE, Rak, GD, Hu, Y, May, MJ, Ma, H-L, Fouser, LA, Sonnenberg, GF, Artis, D
JournalJ Exp Med
Volume212
Issue10
Pagination1513-28
Date Published2015 Sep 21
ISSN1540-9538
Abstract

<p>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.</p>

DOI10.1084/jem.20141831
Alternate JournalJ. Exp. Med.
PubMed ID26371187
PubMed Central IDPMC4577836
Grant List2-P30 CA016520 / CA / NCI NIH HHS / United States
AI061570 / AI / NIAID NIH HHS / United States
AI074878 / AI / NIAID NIH HHS / United States
AI087990 / AI / NIAID NIH HHS / United States
AI095466 / AI / NIAID NIH HHS / United States
AI095608 / AI / NIAID NIH HHS / United States
AI097333 / AI / NIAID NIH HHS / United States
AI102942 / AI / NIAID NIH HHS / United States
AI106697 / AI / NIAID NIH HHS / United States
DP5OD012116 / OD / NIH HHS / United States
F32-AI72943 / AI / NIAID NIH HHS / United States
K08 DK093784 / DK / NIDDK NIH HHS / United States
K08-DK093784 / DK / NIDDK NIH HHS / United States
R01 HL096642 / HL / NHLBI NIH HHS / United States
T32-RR007063 / RR / NCRR NIH HHS / United States