Original Research Intravenous Immunoglobulins Modulate Neutrophil Activation and Vascular Injury Through FcRIII 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 FcRIII and its inhibitory receptor counterpart, FcRIIB, 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 FcRIIB and III abrogated the protective effect of IVIG on acute vaso-occlusive crisis caused by neutrophil recruitment and activation. Analysis of FcRIIB- and FcRIII-deficient mice revealed the predominant expression of FcRIII on circulating neutrophils. FcRIII mediated IVIG-triggered inhibition of leukocyte recruitment, circulating RBC capture, and enhanced Mac-1 activity, whereas FcRIIB was dispensable. In addition, FcRIII-induced IVIG anti-inflammatory activity in neutrophils was mediated by recruitment of Sr