title: Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells.
abstract: The immune mechanisms regulating epithelial cell repair after injury remain poorly defined. We demonstrate here that lymphotoxin beta receptor (LTβR) signaling in intestinal epithelial cells promotes self-repair after mucosal damage. Using a conditional gene-targeted approach, we demonstrate that LTβR signaling in intestinal epithelial cells is essential for epithelial interleukin-23 (IL-23) production and protection against epithelial injury. We further show that epithelial-derived IL-23 promotes mucosal wound healing by inducing the IL-22-mediated proliferation and survival of epithelial cells and mucus production. Additionally, we identified CD4(-)CCR6(+)T-bet(-) RAR-related orphan receptor gamma t (RORγt)(+) lymphoid tissue inducer cells as the main producers of protective IL-22 after epithelial damage. Thus, our results reveal a novel role for LTβR signaling in epithelial cells in the regulation of intestinal epithelial cell homeostasis to limit mucosal damage.
authors.affiliation: Trudeau Institute, Saranac Lake, New York, USA.
authors.forename: E
authors.initials: E
authors.lastname: Macho-Fernandez
authors.affiliation: Trudeau Institute, Saranac Lake, New York, USA.
authors.forename: E P
authors.initials: EP
authors.lastname: Koroleva
authors.affiliation: Trudeau Institute, Saranac Lake, New York, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Spencer
authors.affiliation: Trudeau Institute, Saranac Lake, New York, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tighe
authors.affiliation: Trudeau Institute, Saranac Lake, New York, USA.
authors.forename: E
authors.initials: E
authors.lastname: Torrado
authors.affiliation: Trudeau Institute, Saranac Lake, New York, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Cooper
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Y-X
authors.initials: YX
authors.lastname: Fu
authors.affiliation: Trudeau Institute, Saranac Lake, New York, USA.
authors.forename: A V
authors.initials: AV
authors.lastname: Tumanov
mesh_terms: D000818:Animals; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D006706:Homeostasis; D053759:Interleukin-23 / Q000096:biosynthesis*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D053259:Lymphotoxin beta Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014945:Wound Healing; D000097043:Interleukin-22
chemical_list: D053759:Interleukin-23; D007378:Interleukins; D053259:Lymphotoxin beta Receptor; D000097043:Interleukin-22