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Essential Roles for the Tec Family Kinases Tec and Btk in M-CSF Receptor Signaling Pathways That Regulate Macrophage Survival¹

Martin Melcher^2,*, Bernd Unger^2,, Uwe Schmidt^3,*, Iiro A. Rajantie, Kari Alitalo and Wilfried Ellmeier^4,*

^* Institute of Immunology, Center for Physiology, Pathophysiology and Immunology, Medical University of Vienna, Vienna, Austria; Competence Center for Biomolecular Therapeutics, Vienna, Austria; and Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

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 (GM-CSFR) chain in macrophages but not dendritic cells, implicating Tec family kinases in the lineage-specific regulation of GM-CSFR 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-CSFR expression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the START program (Grant Y-163) of the Fonds zur Förderung der Wissenschaftlichen Forschung and the Austrian Ministry of Education, Science and Culture (to W.E.), by the K-Plus Competence Center for Biomolecular Therapeutics (to W.E.), by the Sonderforschungsbereich project F2305-B13 of the Austrian Research Fund (to W.E.), and by a postdoctoral fellowship (to U.S.) from the Deutsche Forschungsgemeinschaft (Schm 2128/1-1).

² M.M. and B.U. contributed equally to this work.

³ Current address: Nabriva Therapeutics, Brunnerstrasse 59, 1235 Vienna, Austria.

⁴ Address correspondence and reprint requests to Dr. Wilfried Ellmeier, Institute of Immunology, Medical University Vienna, Center for Physiology, Pathophysiology and Immunology, Lazarettgasse 19, A-1090 Vienna, Austria. E-mail address: wilfried.ellmeier{at}meduniwien.ac.at

⁵ Abbreviations used in this paper: BM, bone marrow; BMDC, BM-derived dendritic cell; BMM, BM-derived macrophage; HPRT, hypoxanthine phosphoribosyltransferase; LCM, L929 cell-conditioned medium; M-CSFR, M-CSF receptor; PI, propidium; xid, X-linked immunodeficient (gene); XLA, X-linked agammaglobulinemia.