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PMID: 26371187 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of experimental medicine ·Vol. 212 ·No. 10 ·2015-09-21 ·Pages 1513-28

Giacomin PR, Moy RH, Noti M, Osborne LC, Siracusa MC, Alenghat T, Liu B, McCorkell KA, Troy AE, Rak GD, Hu Y, May MJ, Ma HL, Fouser LA, Sonnenberg GF, Artis D

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.

MeSH Terms
Animals Citrobacter rodentium/pathogenicity Colitis/immunology,pathology Colon/immunology,metabolism,microbiology Cytokines/metabolism Enterobacteriaceae Infections/immunology,mortality Epithelial Cells/metabolism Female I-kappa B Kinase/genetics,immunology,metabolism Immunity, Innate/immunology Interleukins/genetics,metabolism,pharmacology Lymphocytes/immunology,microbiology Male Mice, Inbred C57BL Mice, Mutant Strains Recombinant Proteins/genetics,pharmacology
Chemicals
Cytokines Interleukins Recombinant Proteins I-kappa B Kinase Ikbkb protein, mouse thymic stromal lymphopoietin interleukin-22
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Giacomin Paul R
Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Moy Ryan H
Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Noti Mario
Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Osborne Lisa C
Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104 Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, Cornell University, New York, NY 10021.
Siracusa Mark C
Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Alenghat Theresa
Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Liu Bigang
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957.
McCorkell Kelly A
Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Troy Amy E
Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Rak Gregory D
Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Hu Yinling
Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21701.
May Michael J
Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Ma Hak-Ling
Inflammation and Immunology-Pfizer Biotherapeutics Research and Development, Cambridge, MA 02140.
Fouser Lynette A
Inflammation and Immunology-Pfizer Biotherapeutics Research and Development, Cambridge, MA 02140.
Sonnenberg Gregory F
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, Cornell University, New York, NY 10021.
Artis David
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, Cornell University, New York, NY 10021 dartis@med.cornell.edu.
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20141831
Email
dartis@med.cornell.edu
Published
2015-09-21
Epub
2015-00-14
Pages
1513-28
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC4577836
Subset
IM
Grants
NIAID NIH HHS · R01 AI074878 · United States
NIAID NIH HHS · R01 AI095466 · United States
NIAID NIH HHS · AI061570 · United States
NIAID NIH HHS · F32-AI72943 · United States
NIAID NIH HHS · P01 AI106697 · United States
NIDDK NIH HHS · K08-DK093784 · United States
NIAID NIH HHS · AI102942 · United States
NCRR NIH HHS · T32 RR007063 · United States
NIH HHS · DP5OD012116 · United States
NIH HHS · DP5 OD012116 · United States
NIAID NIH HHS · AI106697 · United States
NIAID NIH HHS · AI074878 · United States
NIAID NIH HHS · AI087990 · United States
NCI NIH HHS · 2-P30 CA016520 · United States
NIAID NIH HHS · R01 AI102942 · United States
NCRR NIH HHS · T32-RR007063 · United States
NHLBI NIH HHS · R01 HL096642 · United States
NIAID NIH HHS · R21 AI087990 · United States
NIAID NIH HHS · AI095608 · United States
NCI NIH HHS · P30 CA016520 · United States
NIDDK NIH HHS · K08 DK093784 · United States
NIAID NIH HHS · U01 AI095608 · United States
NIAID NIH HHS · R01 AI061570 · United States
NIAID NIH HHS · R01 AI097333 · United States
NIAID NIH HHS · AI095466 · United States
NIAID NIH HHS · F32 AI072943 · United States
NIAID NIH HHS · AI097333 · United States
Corrections
CommentIn
PMID: 26392427
External Links
PubMed source DOI: 10.1084/jem.20141831 PMC Full Text View journal details
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