Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM.
Serum IgA is considered a discrete housekeeper of the immune system with multiple anti-inflammatory functions, whereas IgA-immune complexes mediate inflammatory responses. Here, we identify FcalphaRI as a molecular device that determines the nature of IgA responses. In the absence of sustained aggregation, receptor targeting by serum IgA or anti-FcalphaRI Fab inhibits activating responses of heterologous FcgammaR or FcepsilonRI. The inhibitory mechanism involves recruitment of tyrosine phosphatase SHP-1 to FcalphaRI and impairment of Syk, LAT, and ERK phosphorylation induced by FcepsilonRI engagement. SHP-1 recruitment is dependent on ERK. Conversely, sustained aggregation of FcalphaRI by multimeric ligands stimulates cell activation by recruiting high amounts of Syk and aborting SHP-1 binding. Both types of signals require the FcRgamma-ITAM motif. Anti-FcalphaRI Fab treatment suppresses manifestations of allergic asthma in FcalphaRI transgenic mice. These findings redefine FcalphaRI as a bifunctional inhibitory/activating receptor of the immune system that mediates both anti- and proinflammatory functions of IgA.
Pasquier
Benoit
B
INSERM U699, Bichat Medical School, 16 rue Henri Huchard, 75870 Paris Cedex 18, France.
Launay
Pierre
P
Kanamaru
Yutaka
Y
Moura
Ivan C
IC
Pfirsch
Séverine
S
Ruffié
Claude
C
Hénin
Dominique
D
Benhamou
Marc
M
Pretolani
Marina
M
Blank
Ulrich
U
Monteiro
Renato C
RC
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010587:Phagocytosis; D010766:Phosphorylation; D011485:Protein Binding; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011961:Receptors, Fc / Q000378:metabolism / Q000502:physiology*; D017455:Receptors, IgE / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
D015703:Antigens, CD; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D047908:Intracellular Signaling Peptides and Proteins; D011961:Receptors, Fc; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins; D020928:Mitogen-Activated Protein Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse