STIM1 is essential for Fcγ receptor activation and autoimmune inflammation

Abstract

IntroductionPathogenic self-reactive antibody either in the form of soluble immune complexes or as a cellular-bound cytotoxic antibody produces fatal inflammatory responses in human autoimmune disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and hypersensitivity pneumonitis. Previous studies of immune complex-induced tissue injury in rodents have identified the roles of Fc receptors (FcRs) for immunoglobulin G (IgG; Fc␥Rs) and the complement anaphylatoxins (C3a and C5a) as well as their receptors (C3aR and C5aR). [1][2][3] By simultaneous triggering of activating and inhibitory signaling pathways, Fc␥Rs control a wide array of cellular responses, including phagocytosis, antibodydependent cell-mediated cytotoxicity, and release of inflammatory mediators, which ultimately can lead to cellular destruction and the amplification of normal and pathologic immune reactions in vivo. 4,5 In the mouse, there are 3 classes of activating Fc␥Rs: the highaffinity receptor Fc␥RI, the low-affinity receptor Fc␥RIII, and the recently described Fc␥RIV. 3,6 All these Fc␥Rs form heterooligomeric complexes with the same FcR ␥-chain (FcR␥), which contains an immunoreceptor tyrosine-based activation motif (ITAM) sequence that is required for cell activation. 1 IgG ligand crosslinking of FcR␥-associated Fc␥Rs on innate immune cells, such as macrophages, mast cells, natural killer cells, and neutrophils, results in tyrosine phosphorylation of the ITAM with subsequent recruitment of SH2-containing molecules and adaptor proteins that regulate the activation of effector enzymes, including phospholipase (PL) C␥ leading to production of diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP 3 ) followed by influx of extracellular Ca 2ϩ into the cytosol. 3,[7][8][9][10] In immune cells, the predominant pathway of Ca 2ϩ entry is thought to involve IP 3 -receptor mediated Ca 2ϩ release from the endoplasmic reticulum (ER) Ca 2ϩ store, which in turn induces the opening of plasma membrane-expressed store-operated Ca 2ϩ (SOC) channels, also known as calcium release-activated Ca 2ϩ (CRAC) channels by a mechanism known as store-operated Ca 2ϩ entry (SOCE). 11,12 In addition, DAG and some of its metabolites have been shown to induce non-store-operated Ca 2ϩ entry (non-SOCE). 13 Although SOCE has long been recognized as a major pathway of Ca 2ϩ signaling, the principal proteins mediating this process have been discovered only recently. Stromal interaction molecule 1 (STIM1) is an ER-resident Ca 2ϩ sensor that connects ER store depletion to the activation of SOC/CRAC channels. [14][15][16][17] In its N terminus, STIM1 contains an "EF hand" that is located in the ER lumen and binds Ca 2ϩ with low affinity. After store depletion, STIM1 accumulates in regions of ER-plasma membrane appositions (puncta), which appear to be the sites of Ca 2ϩ entry. There it colocalizes with the 4-transmembrane domain protein Orai1 (also called CRACM1), 15,[18][19][20][21] which has b...

An Essential Role of STIM1, Orai1, and S100A8–A9 Proteins for Ca2+ Signaling and FcγR-Mediated Phagosomal Oxidative Activity

“…To our knowledge, we demonstrate for the first time that Orai1 contributes to the regulation of phagosomal oxidative activity through the activation of store depletion-regulated Ca 2+ influx in granulocyte-like HL-60 cells. Moreover, we provide evidence that STIM1 is also involved in this mechanism, in agreement with a recent study (44) in which the STIM1 requirement for the activation of the FcgR-induced Ca 2+ entry and phagocytosis was demonstrated using macrophage Stim1 2/2 mice. All these data support the fact that intraphagosomal oxidative activity occurs through SOCE-induced [Ca 2+ ] i elevation (Fig.…”

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

“…Interestingly, production and secretion of MCP-1 was not affected by Selk-deficiency. This is consistent with findings in which macrophages for the ER membrane protein crucial for Ca 2 + flux, Stim1, were not different from wild-type macrophages in FccR-induced MCP-1 secretion (26). This very likely affects the special role that chemokines like MCP-1 play in attracting monocytes and macrophages for both inflammatory functions as well and noninflammatory functions such as engulfment of apoptotic cells and wound-healing (162).…”

“…On efflux of Ca 2 + from ER stores, STIM1 is induced to interact with CRAC channels, causing structural changes in the CRAC channel that allows extracellular Ca 2 + to enter the cytosol. Stim1 knockout mice were used to demonstrate that SOCE was important for FccR-mediated phagocytosis by macrophages (26). Both Ca 2 + flux and ROS feed into NFjB activation, and Se supplementation of macrophages to above-adequate levels may be particularly disruptive for the redox balance that regulates NFjB signaling.…”

Role of the Neutrophil NADPH Oxidase and S100A8/A9 in the Pathophysiology of Chronic Inflammation

“…Ca 2+ influx appears to be necessary for an optimal intraphagosomal oxidative activity but not sufficient to initiate oxidative activation (Dewitt et al, 2002). Orai1 and STIM1 contribute to the regulation of phagosomal NOX2 activity through the activation of store depletion-regulated Ca 2+ influx (Braun et al, 2009;Steinckwich et al, 2011). On the other hand, Itagaki et al (Itagaki et al, 2005) suggest that Ca 2+ influx occurring through a mechanism other than SOCE could be a relevant event to activate NOX2.…”