LynA regulates an inflammation-sensitive signaling checkpoint in macrophages
Tanya S Freedman,
Ying X Tan,
Katarzyna M Skrzypczynska,
Boryana N Manz,
Frances V Sjaastad,
Helen S Goodridge,
Clifford A Lowell,
Arthur Weiss
Affiliations
Tanya S Freedman
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
Ying X Tan
Russell/Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States
Katarzyna M Skrzypczynska
Russell/Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States
Boryana N Manz
Russell/Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, United States
Frances V Sjaastad
Department of Pharmacology, Center for Immunology, University of Minnesota, Minneapolis, United States
Helen S Goodridge
Regenerative Medicine Institute and Research Division of Immunology, Cedars-Sinai Medical Center, Los Angeles, United States
Clifford A Lowell
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, United States
Arthur Weiss
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
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.
