title: Lyn deficiency leads to increased microbiota-dependent intestinal inflammation and susceptibility to enteric pathogens.
abstract: The Lyn tyrosine kinase governs the development and function of various immune cells, and its dysregulation has been linked to malignancy and autoimmunity. Using models of chemically induced colitis and enteric infection, we show that Lyn plays a critical role in regulating the intestinal microbiota and inflammatory responses as well as protection from enteric pathogens. Lyn(-/-) mice were highly susceptible to dextran sulfate sodium (DSS) colitis, characterized by significant wasting, rectal bleeding, colonic pathology, and enhanced barrier permeability. Increased DSS susceptibility in Lyn(-/-) mice required the presence of T but not B cells and correlated with dysbiosis and increased IFN-γ(+) and/or IL-17(+) colonic T cells. This dysbiosis was characterized by an expansion of segmented filamentous bacteria, associated with altered intestinal production of IL-22 and IgA, and was transmissible to wild-type mice, resulting in increased susceptibility to DSS. Lyn deficiency also resulted in an inability to control infection by the enteric pathogens Salmonella enterica serovar Typhimurium and Citrobacter rodentium. Lyn(-/-) mice exhibited profound cecal inflammation, bacterial dissemination, and morbidity following S. Typhimurium challenge and greater colonic inflammation throughout the course of C. rodentium infection. These results identify Lyn as a key regulator of the mucosal immune system, governing pathophysiology in multiple models of intestinal disease.
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Roberts
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bishop
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
authors.forename: Xueling
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Beer
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada; and.
authors.forename: Winnie W S
authors.initials: WW
authors.lastname: Kum
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Krebs
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
authors.forename: Morris
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada; and.
authors.forename: Navkiran
authors.initials: N
authors.lastname: Gill
authors.affiliation: Child and Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: John J
authors.initials: JJ
authors.lastname: Priatel
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada; and.
authors.forename: B Brett
authors.initials: BB
authors.lastname: Finlay
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; kharder@mail.ubc.ca.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Harder
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000382:microbiology; D044082:Citrobacter rodentium / Q000276:immunology / Q000472:pathogenicity; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016264:Dextran Sulfate; D004198:Disease Susceptibility; D064806:Dysbiosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005260:Female; D015870:Gene Expression; D007070:Immunoglobulin A / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000097043:Interleukin-22
chemical_list: D016264:Dextran Sulfate; D007070:Immunoglobulin A; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D019061:src-Family Kinases; D000097043:Interleukin-22; C060902:lyn protein-tyrosine kinase