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‐mediated Ca2+ responses consist of complex mechanisms 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 Fcγ‐receptor activation and IgG‐induced inflammation. Here, we identify the closely related STIM2 as mediator 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 and without a strict requirement for Ca2+ influx. While STIM2 also contributes in part to FcγR 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.

[1]  S. Houser,et al.  Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. , 2013, The Journal of clinical investigation.

[2]  M. Prakriya,et al.  Permeation, selectivity and gating in store‐operated CRAC channels , 2012, The Journal of physiology.

[3]  M. Madesh,et al.  STIM proteins: dynamic calcium signal transducers , 2012, Nature Reviews Molecular Cell Biology.

[4]  S. Beer-Hammer,et al.  Defective Macrophage Migration in Gαi2- but Not Gαi3-Deficient Mice , 2012, The Journal of Immunology.

[5]  H. Anders,et al.  Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. , 2011, Kidney international.

[6]  T. Wynn,et al.  Protective and pathogenic functions of macrophage subsets , 2011, Nature Reviews Immunology.

[7]  A. Sica,et al.  Macrophages in cancer and infectious diseases: the 'good' and the 'bad'. , 2011, Immunotherapy.

[8]  B. Nieswandt,et al.  STIM and Orai in platelet function. , 2011, Cell calcium.

[9]  M. Holtzman,et al.  Alternatively activated macrophages and airway disease. , 2011, Chest.

[10]  Y. Baba,et al.  The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. , 2011, Immunity.

[11]  D. Remick,et al.  The pathogenesis of sepsis. , 2011, Annual review of pathology.

[12]  John D Lambris,et al.  Complement: a key system for immune surveillance and homeostasis , 2010, Nature Immunology.

[13]  J. Putney.  Pharmacology of store-operated calcium channels. , 2010, Molecular interventions.

[14]  S. Akira,et al.  The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors , 2010, Nature Immunology.

[15]  H. Wiendl,et al.  Stromal Interaction Molecules 1 and 2 Are Key Regulators of Autoreactive T Cell Activation in Murine Autoimmune Central Nervous System Inflammation , 2009, The Journal of Immunology.

[16]  B. Nieswandt,et al.  Both FcγRIV and FcγRIII are essential receptors mediating type II and type III autoimmune responses via FcRγ‐LAT‐dependent generation of C5a , 2009, European journal of immunology.

[17]  J. Eilers,et al.  STIM2 Regulates Capacitive Ca2+ Entry in Neurons and Plays a Key Role in Hypoxic Neuronal Cell Death , 2009, Science Signaling.

[18]  Y. Baba,et al.  Physiological function and molecular basis of STIM1‐mediated calcium entry in immune cells , 2009, Immunological reviews.

[19]  G. Wanner,et al.  Cross-Talk between TLR4 and FcγReceptorIII (CD16) Pathways , 2009, PLoS pathogens.

[20]  B. Nieswandt,et al.  STIM1 is essential for Fcgamma receptor activation and autoimmune inflammation. , 2009, Blood.

[21]  Y. Shimizu,et al.  Characterization of YM-58483/BTP2, a novel store-operated Ca2+ entry blocker, on T cell-mediated immune responses in vivo. , 2008, International immunopharmacology.

[22]  Onn Brandman,et al.  Feedback Loops Shape Cellular Signals in Space and Time , 2008, Science.

[23]  T. Renné,et al.  The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction , 2008, The Journal of experimental medicine.

[24]  E. Lamperti,et al.  Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance , 2008, Nature Immunology.

[25]  R. Penner,et al.  STIM2 protein mediates distinct store‐dependent and store‐independent modes of CRAC channel activation , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  B. Holzmann,et al.  Role of Toll-like receptor responses for sepsis pathogenesis. , 2008, Immunobiology.

[27]  Onn Brandman,et al.  STIM2 Is a Feedback Regulator that Stabilizes Basal Cytosolic and Endoplasmic Reticulum Ca2+ Levels , 2007, Cell.

[28]  P. Monk,et al.  Function, structure and therapeutic potential of complement C5a receptors , 2007, British journal of pharmacology.

[29]  S. Feske.  Calcium signalling in lymphocyte activation and disease , 2007, Nature Reviews Immunology.

[30]  J. Putney.  Recent breakthroughs in the molecular mechanism of capacitative calcium entry (with thoughts on how we got here). , 2007, Cell calcium.

[31]  K. Honda,et al.  YM-58483, a selective CRAC channel inhibitor, prevents antigen-induced airway eosinophilia and late phase asthmatic responses via Th2 cytokine inhibition in animal models. , 2007, European journal of pharmacology.

[32]  M. Erard,et al.  Potent inhibition of store‐operated Ca2+ influx and superoxide production in HL60 cells and polymorphonuclear neutrophils by the pyrazole derivative BTP2 , 2007, Journal of leukocyte biology.

[33]  A. Blom,et al.  Toll-like receptor 4 induced FcγR expression potentiates early onset of joint inflammation and cartilage destruction during immune complex arthritis: Toll-like receptor 4 largely regulates FcγR expression by interleukin 10 , 2006, Annals of the rheumatic diseases.

[34]  J. Kinet,et al.  A Pyrazole Derivative Potently Inhibits Lymphocyte Ca2+ Influx and Cytokine Production by Facilitating Transient Receptor Potential Melastatin 4 Channel Activity , 2006, Molecular Pharmacology.

[35]  S. Akira,et al.  Pathogen Recognition and Innate Immunity , 2006, Cell.

[36]  R. Schmidt,et al.  Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice. , 2006, The Journal of clinical investigation.

[37]  R. Schmidt,et al.  Fc receptors and their interaction with complement in autoimmunity. , 2005, Immunology letters.

[38]  Tobias Meyer,et al.  STIM Is a Ca2+ Sensor Essential for Ca2+-Store-Depletion-Triggered Ca2+ Influx , 2005, Current Biology.

[39]  P. Bruhns,et al.  FcγRIV : A novel FcR with distinct IgG subclass specificity , 2005 .

[40]  L. Birnbaumer,et al.  Macrophages Induce the Inflammatory Response in the Pulmonary Arthus Reaction through Gαi2 Activation That Controls C5aR and Fc Receptor Cooperation1 , 2005, The Journal of Immunology.

[41]  J. Köhl,et al.  C5a Initiates the Inflammatory Cascade in Immune Complex Peritonitis1 , 2004, The Journal of Immunology.

[42]  J. Putney,et al.  Mechanisms of phospholipase C-regulated calcium entry. , 2004, Current molecular medicine.

[43]  Shizuo Akira,et al.  TLR signaling pathways. , 2004, Seminars in immunology.

[44]  M. Berridge,et al.  Calcium: Calcium signalling: dynamics, homeostasis and remodelling , 2003, Nature Reviews Molecular Cell Biology.

[45]  R. Schmidt,et al.  C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease. , 2002, The Journal of clinical investigation.

[46]  P. Heeringa,et al.  Opposite Regulation of Type II and III Receptors for Immunoglobulin G in Mouse Glomerular Mesangial Cells and in the Induction of Anti-glomerular Basement Membrane (GBM) Nephritis* , 2002, The Journal of Biological Chemistry.

[47]  M. Walport,et al.  Complement Activation Selectively Potentiates the Pathogenicity of the IgG2b and IgG3 Isotypes of a High Affinity Anti-Erythrocyte Autoantibody , 2002, The Journal of experimental medicine.

[48]  J. Westwick,et al.  Receptor-operated Ca2+ influx channels in leukocytes: a therapeutic target? , 2002, Trends in pharmacological sciences.

[49]  P. Watkins,et al.  Experimental models of Gram‐negative sepsis , 2001, The British journal of surgery.

[50]  R. Schmidt,et al.  FcγRIII (CD16)-Deficient Mice Show IgG Isotype-Dependent Protection to Experimental Autoimmune Hemolytic Anemia , 1998 .

[51]  H. Heiken,et al.  The IgG Fc receptor family , 1998, Annals of Hematology.

[52]  R. Tsien,et al.  A new generation of Ca2+ indicators with greatly improved fluorescence properties. , 1985, The Journal of biological chemistry.

[53]  B. Nieswandt,et al.  STIM1 is essential for Fcreceptor activation and autoimmune inflammation , 2013 .

[54]  T. Hirano,et al.  Essential function for the calcium sensor STIM1 in mast cell activation and anaphylactic responses , 2008, Nature Immunology.

[55]  J. Ravetch,et al.  Fcγ receptors as regulators of immune responses , 2008, Nature Reviews Immunology.

[56]  S Gordon,et al.  Macrophage receptors and immune recognition. , 2005, Annual review of immunology.

[57]  Tobias Meyer,et al.  STIM Is a Ca 2+ Sensor Essential for Ca 2+ -Store-Depletion-Triggered Ca 2+ Influx , 2005 .