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The role of the Lyn tyrosine kinase in innate immunity and intestinal inflammation

University of British Columbia

The immune system is critical for host survival by providing protection against infectious organisms. However, the immune system also plays a major pathological role in many human diseases through inappropriate inflammatory responses that can lead to tissue damage and death. Therefore, understanding the mechanisms that drive and regulate these responses has broad implications for the development of therapies for numerous diseases including inflammatory bowel disease and atherosclerosis. Through its involvement in key signalling pathways, the Lyn tyrosine kinase is an important regulator of immune cell development and function. Using models of chemically induced colitis and enteric infection, we show that Lyn plays a critical role in regulating gastro-intestinal inflammation and in protection from enteric pathogens, by regulating host responses to intestinal microbes. Lyn-/- mice were highly susceptible to dextran sulfate sodium-induced colitis, whereas Lyn gain-of-function (LynUP) mice exhibited attenuated colitis. Protection in LynUP mice was independent of the adaptive immune system and involved hypersensitivity to microbial products such as LPS, leading to enhanced production of protective factors including IL-22. Increased DSS susceptibility in Lyn-/- mice correlated with dysbiosis and altered T cell responses. This dysbiosis was characterized by an expansion of segmented filamentous bacteria, which was associated with altered production of IL-22 and IgA. Furthermore, increased Lyn activity in dendritic cells was sufficient to drive increased IL-22 production by innate lymphoid cells. This extended beyond the gut to the spleen, which added to previous findings by our lab and others, identifying Lyn as an important regulator of systemic mononuclear phagocytes and their inflammatory responses. Finally, we identified Lyn as a negative regulator of Ly6C- patrolling monocytes (pMo). Lyn-/- mice displayed increased frequency and numbers of pMos whereas LynUP mice were skewed towards increased conventional monocytes (cMo). The increase in pMos in Lyn-/- mice was independent of the adaptive immune system and the autoimmune and myeloproliferative disorders that develop in these mice with age. Furthermore, these monocyte differences correlated with a pathological role for Lyn in a model of atherosclerosis. Together, these studies identify Lyn as an important regulator of innate immune responses involved in sterile and microbial-driven inflammatory diseases.

Text

2020-07-31

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/54079

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/