Essential roles for the Tec family kinases Tec and Btk in M-CSF receptor signaling pathways that regulate macrophage survival.
Tec family kinases have important roles in lymphocytes; however, little is known about their function in monocytes/macrophages. In this study we report that Tec family kinases are essential for M-CSF (M-CSF)-induced signaling pathways that regulate macrophage survival. Compared with wild-type bone marrow-derived macrophage (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 the GM-CSF receptor alpha (GM-CSFRalpha) chain in macrophages but not dendritic cells, implicating Tec family kinases in the lineage-specific regulation of GM-CSFRalpha 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-CSFRalpha expression.
Institute of Immunology, Center for Physiology, Pathophysiology and Immunology, Medical University of Vienna, Vienna, Austria.
Martin
M
Melcher
Bernd
B
Unger
Uwe
U
Schmidt
Iiro A
IA
Rajantie
Kari
K
Alitalo
Wilfried
W
Ellmeier
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D053471:Caspases, Initiator; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family / Q000276:immunology; D022423:Myeloid Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*
D021122:Protein Subunits; D016173:Macrophage Colony-Stimulating Factor; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D000077329:Agammaglobulinaemia Tyrosine Kinase; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator