Essential roles for the Tec family kinases Tec and Btk in M-CSF receptor signaling pathways that regulate macrophage survival

摘要

Tec family kinases have important roles in lymphocytes, however little is known about their function in monocytes/macrophages. Here we report that Tec family kinases are essential for macrophage colony stimulating factor (M-CSF)-induced signaling pathways that regulate macrophage survival. Compared to wildtype bone marrow-derived macrophages (BMM) cultures, Tec−/−Btk−/− BMM cultures displayed increased cell death that correlated with a severe drop in macrophage numbers. In addition, macrophages deficient in either Tec or Btk showed expression and activation of caspase-11. Elucidation of M-CSF receptor (M-CSFR) signaling pathways revealed that the total tyrosine phosphorylation pattern upon M-CSF stimulation was altered in Tec−/−Btk−/− macrophages despite normal expression and phosphorylation of the M-CSFR. Further, Tec and Btk are required for proper expression of GM-CSF receptor alpha (GM-CSFRα) chain in macrophages but not dendritic cells, implicating Tec family kinases in the lineage-specific regulation of GM-CSFRα expression. Taken together, our study shows that Tec and Btk regulate M-CSFR signaling-induced macrophage survival and provides a novel link between Tec family kinases and the regulation of caspase-11 and GM-CSFRα expression.