Orchestration of immune function through STIM1-modulated calcium signaling in murine microglia

Abstract

It is well established that the differentiation of microglia into active immune cells is governed by increase of sustained intracellular Ca2+ concentration ([Ca2+]i) in the cytoplasm, which is maintained by SOCE (store-operated calcium entry). Acute movements of immune cells are also controlled by Ca2+ signaling, especially by changes in the Ca2+ concentration within micro-domains ([Ca2+]micro-domains) at the cell periphery. The role of STIM1 in chronic and global [Ca2+]i changes, which governs the proliferation, gene expression and differentiation into active immune cells, has been well examined. However, the role of STIM1 in regulating peripheral [Ca2+]micro-domains in immune cells, including microglia, has not been studied yet. In this study, we found that murine Stim1-/- microglia showed severe defects in their acute movements, including purinergic stimulation-induced phagocytosis and chemotaxis, which is controlled by Ca2+ signaling in [Ca2+]micro-domains. Interestingly, Stim1-/- microglia exhibited highly fluctuating local [Ca2+]micro-domains changes at the cell periphery, and these fluctuations disappeared completely once mitochondrial membrane potential disruptors were added. Stim1-/- microglia also show attenuated movements of Oria1 upon amoeboid shape-change induced by LPS, which seems to be related to the partial reduction in [Ca2+]micro-domains fluctuations achieved by SOCE inhibitors. Our new discovery indicates that STIM1 is a critical controller of the local [Ca2+]micro-domains, not only through its regulation of SOCE pores, but also through its coordination of mitochondrial Ca2+ buffering capacity in micro-domains of the cell periphery

In conclusion, STIM1 is a fundamental regulator of the Ca2+ signaling that is required for proper immune functioning of microglia. In that process, in addition to regulating sustained [Ca2+]i changes, STIM1 also controls [Ca2+]micro-domains changes through coordinating mitochondrial Ca2+ buffering capacity via local SOCE pores.