title: LynA regulates an inflammation-sensitive signaling checkpoint in macrophages.
abstract: Clustering of receptors associated with immunoreceptor tyrosine-based activation motifs (ITAMs) initiates the macrophage antimicrobial response. ITAM receptors engage Src-family tyrosine kinases (SFKs) to initiate phagocytosis and macrophage activation. Macrophages also encounter nonpathogenic molecules that cluster receptors weakly and must tune their sensitivity to avoid inappropriate responses. To investigate this response threshold, we compared signaling in the presence and absence of receptor clustering using a small-molecule inhibitor of Csk, which increased SFK activation and produced robust membrane-proximal signaling. Surprisingly, receptor-independent SFK activation led to a downstream signaling blockade associated with rapid degradation of the SFK LynA. Inflammatory priming of macrophages upregulated LynA and promoted receptor-independent signaling. In contrast, clustering the hemi-ITAM receptor Dectin-1 induced signaling that did not require LynA or inflammatory priming. Together, the basal-state signaling checkpoint regulated by LynA expression and degradation and the signaling reorganization initiated by receptor clustering allow cells to discriminate optimally between pathogens and nonpathogens.
authors.affiliation: Russell/Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States.|Department of Pharmacology, Center for Immunology, University of Minnesota, Minneapolis, United States.
authors.forename: Tanya S
authors.initials: TS
authors.lastname: Freedman
authors.affiliation: Russell/Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Ying X
authors.initials: YX
authors.lastname: Tan
authors.affiliation: Russell/Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Skrzypczynska
authors.affiliation: Russell/Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Boryana N
authors.initials: BN
authors.lastname: Manz
authors.affiliation: Department of Pharmacology, Center for Immunology, University of Minnesota, Minneapolis, United States.
authors.forename: Frances V
authors.initials: FV
authors.lastname: Sjaastad
authors.affiliation: Regenerative Medicine Institute and Research Division of Immunology, Cedars-Sinai Medical Center, Los Angeles, United States.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Goodridge
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.affiliation: Russell/Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States.|Howard Hughes Medical Institute, University of California, San Francisco, Chevy Chase, United States.
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
mesh_terms: D000818:Animals; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases
keywords: ITAMs; Src-family kinases; biochemistry; cell signaling; immunology; innate immunity; macrophages; mouse; receptors