title: Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity.
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.
authors.affiliation: Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Giacomin
authors.affiliation: Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Moy
authors.affiliation: Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Mario
authors.initials: M
authors.lastname: Noti
authors.affiliation: 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.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Osborne
authors.affiliation: Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Siracusa
authors.affiliation: Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Theresa
authors.initials: T
authors.lastname: Alenghat
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957.
authors.forename: Bigang
authors.initials: B
authors.lastname: Liu
authors.affiliation: Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: McCorkell
authors.affiliation: Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Troy
authors.affiliation: Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Rak
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21701.
authors.forename: Yinling
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Perelman School of Medicine and School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: May
authors.affiliation: Inflammation and Immunology-Pfizer Biotherapeutics Research and Development, Cambridge, MA 02140.
authors.forename: Hak-Ling
authors.initials: HL
authors.lastname: Ma
authors.affiliation: Inflammation and Immunology-Pfizer Biotherapeutics Research and Development, Cambridge, MA 02140.
authors.forename: Lynette A
authors.initials: LA
authors.lastname: Fouser
authors.affiliation: Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, Cornell University, New York, NY 10021.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Sonnenberg
authors.affiliation: Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, Cornell University, New York, NY 10021 dartis@med.cornell.edu.
authors.forename: David
authors.initials: D
authors.lastname: Artis
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium / Q000472:pathogenicity; D003092:Colitis / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000401:mortality; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007113:Immunity, Innate / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008214:Lymphocytes / Q000276:immunology* / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D000094632:Thymic Stromal Lymphopoietin; D000097043:Interleukin-22
chemical_list: D016207:Cytokines; D051550:I-kappa B Kinase; D007378:Interleukins; D011994:Recombinant Proteins; D000094632:Thymic Stromal Lymphopoietin; D000097043:Interleukin-22; C496562:Ikbkb protein, mouse