Intravenous Immunoglobulins Modulate Neutrophil Activation and Vascular Injury Through FcγRIII and SHP-1

Rationale: Intravascular neutrophil recruitment and activation are key pathogenic factors that contribute to vascular injury. Intravenous immunoglobulin (IVIG) has been shown to have a beneficial effect in systemic inflammatory disorders; however, the mechanisms underlying IVIG's inhibitory effect on neutrophil recruitment and activation are not understood. Objective: We studied the mechanisms by which IVIG exerts protection from neutrophil-mediated acute vascular injury. Methods and Results: We examined neutrophil behavior in response to IVIG in vivo, using real-time intravital microscopy. We found that an antibody that blocks both Fc gamma RIII and its inhibitory receptor counterpart, Fc gamma RIIB, abrogated the inhibitory effect of IVIG on leukocyte recruitment and heterotypic red blood cell (RBC) interactions with adherent leukocytes in wild-type mice. In the context of sickle cell disease, the blockade of both Fc gamma RIIB and III abrogated the protective effect of IVIG on acute vaso-occlusive crisis caused by neutrophil recruitment and activation. Analysis of Fc gamma RIIB- and Fc gamma RIII-deficient mice revealed the predominant expression of Fc gamma RIII on circulating neutrophils. Fc gamma RIII mediated IVIG-triggered inhibition of leukocyte recruitment, circulating RBC capture, and enhanced Mac-1 activity, whereas Fc gamma RIIB was dispensable. In addition, Fc gamma RIII-induced IVIG anti-inflammatory activity in neutrophils was mediated by recruitment of Src homology 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1). Indeed, the protective effect of IVIG on leukocyte recruitment and activation was abrogated in SHP-1-mutant mice. Conclusions: Fc gamma RIII, a classic activating receptor, has an unexpected inhibitory role on neutrophil adhesion and activation via recruitment of SHP-1 in response to IVIG. Our results identify SHP-1 as a therapeutic target in neutrophil-mediated vascular injury. (Circ Res. 2012;110:1057-1066.)