title: mTOR Mediates IL-23 Induction of Neutrophil IL-17 and IL-22 Production.
abstract: It has been shown recently that neutrophils are able to produce IL-22 and IL-17, which differentially regulate the pathogenesis of inflammatory bowel disease. However, it is still largely unknown how the neutrophil production of IL-22 and IL-17 is regulated, and their role in the pathogenesis of inflammatory bowel disease. In this study, we found that IL-23 promoted neutrophil production of IL-17 and IL-22. IL-23 stimulated the neutrophil expression of IL-23R as well as rorc and ahr. Retinoid acid receptor-related orphan receptor γ t and aryl-hydrocarbon receptor differentially regulated IL-23 induction of neutrophil IL-17 and IL-22. In addition, IL-23 induced the activation of mTOR in neutrophils. Blockade of the mTOR pathway inhibited IL-23-induced expression of rorc and ahr, as well as IL-17 and IL-22 production. By using a microbiota Ag-specific T cell-mediated colitis model, we demonstrated that depletion of neutrophils, as well as blockade of IL-22, resulted in a significant increase in the severity of colitis, thereby indicating a protective role of neutrophils and IL-22 in chronic colitis. Collectively, our data revealed that neutrophils negatively regulate microbiota Ag-specific T cell induction of colitis, and IL-23 induces neutrophil production of IL-22 and IL-17 through induction of rorc and ahr, which is mediated by the mTOR pathway.
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555;
authors.forename: Feidi
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555;
authors.forename: Anthony
authors.initials: A
authors.lastname: Cao
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555;
authors.forename: Suxia
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555;
authors.forename: Heather L
authors.initials: HL
authors.lastname: Evans-Marin
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555; Department of Gastroenterology, The Qilu Hospital, Shandong University, Shandong 250012, China;
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555; Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555; Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555; and.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Carlsen
authors.affiliation: Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555; and.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Dann
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555;
authors.forename: Lynn
authors.initials: L
authors.lastname: Soong
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555;
authors.forename: Jiaren
authors.identifier: 0000-0001-5084-4437
authors.initials: J
authors.lastname: Sun
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ 08540.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555; yicong@utmb.edu.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Cong
mesh_terms: D000818:Animals; D002432:Cecum / Q000473:pathology; D002454:Cell Differentiation; D003092:Colitis / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000378:metabolism* / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D058504:Th17 Cells / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D019869:Phosphatidylinositol 3-Kinases; D018336:Receptors, Aryl Hydrocarbon; D018123:Receptors, Interleukin; D058570:TOR Serine-Threonine Kinases; D000097043:Interleukin-22; C528688:interleukin-23 receptor, mouse; C546843:mTOR protein, mouse