Submitted May 27, 2008
Accepted October 2, 2008
STIM1 is essential for Fc
receptor activation and autoimmune inflammation
Attila Braun, J. Engelbert Gessner, David Varga-Szabo, Shahzad N. Syed, Stephanie Konrad, David Stegner, Timo Vogtle, Reinhold E. Schmidt, and Bernhard Nieswandt*
University of Wurzburg, Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Wurzburg, Germany
Hanover Medical School, Molecular Immunology Research Unit, Clinic for Immunology and Rheumatology, Hanover, Germany
Institute of Clinical Biochemistry and Pathobiochemistry, University of Wurzburg, Wurzburg, Germany
* Corresponding author; email: bernhard.nieswandt{at}virchow.uni-wuerzburg.de.
Fc
receptors (FcRs) on mononuclear phagocytes trigger autoantibody and immune complex-induced diseases through coupling the self-reactive IgG response to innate effector pathways, such as phagocytosis, and the recruitment of inflammatory cells. FcR-based activation is critical in the pathogenesis of these diseases, although the contribution of FcR-mediated calcium signaling in autoimmune injury is unclear. Here we show that macrophages lacking the endoplasmic reticulum resident calcium sensor STIM1 cannot activate FcR-induced Ca2+ entry and phagocytosis. As a direct consequence, STIM1 deficiency results in resistance to experimental immune thrombocytopenia and anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis. These results establish STIM1 as a novel and essential component of FcR activation and also indicate that inhibition of STIM1-dependent signaling might become a new strategy to prevent or treat IgG-dependent immunological diseases.
