Cooperative and alternate functions for STIM1 and STIM2 in macrophage activation and in the context of inflammation

Calcium (Ca2+) signaling in immune cells, including macrophages, controls a wide range of effector functions that are critical for host defense and contribute to inflammation and autoimmune diseases. However, receptor-mediatedCa(2+) responses consist of complexmechanisms that make it difficult to identify the pathogenesis and develop therapy. Previous studies have revealed the importance of the Ca2+ sensor STIM1 and store-operated Ca2+-entry (SOCE) for Fc gamma-receptor activation and IgG-induced inflammation. Here, we identify the closely related STIM2 asmediator of cell migration and cytokine production downstream of GPCR and TLR4 activation in macrophages and show that mice lacking STIM2 are partially resistant to inflammatory responses in peritonitis and LPS-induced inflammation. Interestingly, STIM2 modulates the migratory behavior of macrophages independent from STIM1 andwithout a strict requirement for Ca2+ influx. While STIM2 also contributes in part to Fc gamma R activation, the C5a-induced amplification of IgG-mediated phagocytosis is mainly dependent on STIM1. Blockade of STIM-related functions limits mortality in experimental models of AIHA and LPS-sepsis in normal mice. These results suggest benefits of Ca2+- inhibition for suppression of exacerbated immune reactions and illustrate the significance of alternate functions of STIM proteins in macrophage activation and in the context of innate immune inflammation.