Recent publications from Dr. Harder Lab

Lyn Deficiency Leads to Increased Microbiota-Dependent Intestinal Inflammation and Susceptibility to Enteric Pathogens


J Immunol. 2014 Oct 22. pii: 1302832


http://www.jimmunol.org/content/193/10/5249.long


Roberts ME1, Bishop JL1, Fan X1, Beer JL1, Kum WW2, Krebs DL1, Huang M1, Gill N2, Priatel JJ3, Finlay BB2, Harder KW4.


  • 1Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
  • 2Department 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.
  • 3Child and Family Research Institute, Vancouver, British Columbia V5Z 4H4, Canada.
  • 4Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; kharder@mail.ubc.ca.

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.


Copyright © 2014 by The American Association of Immunologists, Inc.