Orai1 controls C5a-induced neutrophil recruitment in inflammation.
Stromal interaction molecule 1 (STIM1)-dependent store operated calcium-entry (SOCE) through Orai1-mediated calcium (Ca(2+) ) influx is considered a major pathway of Ca(2+) signaling, serving T-cell, mast cell, and platelet responses. Here, we show that Orai1 is critical for neutrophil function. Orai1-deficient neutrophils present defects in fMLP and complement C5a-induced Ca(2+) influx and migration, although they respond normally to another chemoattractant, CXCL2. Up until now, no specific contribution of Orai1 independent from STIM1 or SOCE has been recognized in immune cells. Here, we observe that Orai1-deficient neutrophils exhibit normal STIM1-dependent SOCE and STIM1-deficient neutrophils respond to fMLP and C5a efficiently. Despite substantial cytokine production, Orai1(-/-) chimeric mice show impaired neutrophil recruitment in LPS-induced peritonitis. Moreover, Orai1 deficiency results in profoundly defective C5a-triggered neutrophil lung recruitment in hypersensitivity pneumonitis. Comparative evaluation of inflammation in Stim1(-/-) chimeras reveals a distinct pathogenic contribution of STIM1, including its involvement in IgG-induced C5a production. Our data establish Orai1 as key signal mediator of C5aR activation, contributing to inflammation by a STIM1-independent pathway of Ca(2+) -influx in neutrophils.
Clinical Department of Immunology and Rheumatology, Hannover Medical School, Germany.
Georgios
G
Sogkas
Chair of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Germany.
Timo
T
Vögtle
Clinical Department of Immunology and Rheumatology, Hannover Medical School, Germany.
Eduard
E
Rau
Clinical Department of Immunology and Rheumatology, Hannover Medical School, Germany.
Britta
B
Gewecke
Chair of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Germany.
David
D
Stegner
Clinical Department of Immunology and Rheumatology, Hannover Medical School, Germany.
Reinhold E
RE
Schmidt
Chair of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Germany.
Bernhard
B
Nieswandt
Clinical Department of Immunology and Rheumatology, Hannover Medical School, Germany.
J Engelbert
JE
Gessner
D000818:Animals; D015220:Calcium Channels / Q000276:immunology*; D015936:Complement C5a / Q000276:immunology*; D005260:Female; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology*; D000071740:ORAI1 Protein; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology
D015220:Calcium Channels; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a
Calcium; Complement; Fcγ receptors; Inflammation; Neutrophil