title: Lyn-dependent signaling regulates the innate immune response by controlling dendritic cell activation of NK cells.
abstract: The innate immune response is a first line of defense against invading pathogens; however, the magnitude of this response must be tightly regulated, as hyper- or suboptimal responses can be detrimental to the host. Systemic inflammation resulting from bacterial infection can lead to sepsis, which remains a serious problem with high mortality rates. Lyn tyrosine kinase plays a key role in adaptive immunity, although its role in innate immunity remains unclear. In this study, we show that Lyn gain-of-function (Lyn(up/up)) mice display enhanced sensitivity to endotoxin and succumb to upregulated proinflammatory cytokine production at a dose well tolerated by control animals. Endotoxin sensitivity in Lyn(up/up) mice depends on dendritic cells (DCs) and NK cells and occurs though a mechanism involving increased maturation and activation of the DC compartment, leading to elevated production of IFN-γ by NK cells. We further show that modulation of endotoxin-induced signal transduction in DCs by Lyn involves the phosphatases Src homology 2 domain-containing phosphatase-1 and SHIP-1. Collectively, we demonstrate that Lyn regulates DC physiology such that alterations in Lyn-dependent signaling have profound effects on the nature and magnitude of inflammatory responses. Our studies highlight how perturbations in signaling pathways controlling DC/NK cell-regulated responses to microbial products can profoundly affect the magnitude of innate immune responses.
authors.affiliation: Department of Microbiology and Immunology, I3 Research Group, Life Sciences Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Krebs
authors.forename: Manreet K
authors.initials: MK
authors.lastname: Chehal
authors.forename: Alexander
authors.initials: A
authors.lastname: Sio
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huntington
authors.forename: Mei Lin
authors.initials: ML
authors.lastname: Da
authors.forename: Pascal
authors.initials: P
authors.lastname: Ziltener
authors.forename: Melissa
authors.initials: M
authors.lastname: Inglese
authors.forename: Nicole
authors.initials: N
authors.lastname: Kountouri
authors.forename: John J
authors.initials: JJ
authors.lastname: Priatel
authors.forename: Jessica
authors.initials: J
authors.lastname: Jones
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Harder
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019061:src-Family Kinases / Q000172:deficiency / Q000502:physiology*
chemical_list: D007371:Interferon-gamma; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases