| First Author | Jang JE | Year | 2012 |
| Journal | Circ Res | Volume | 110 |
| Issue | 8 | Pages | 1057-66 |
| PubMed ID | 22415018 | Mgi Jnum | J:212521 |
| Mgi Id | MGI:5581599 | Doi | 10.1161/CIRCRESAHA.112.266411 |
| Citation | Jang JE, et al. (2012) Intravenous immunoglobulins modulate neutrophil activation and vascular injury through FcgammaRIII and SHP-1. Circ Res 110(8):1057-66 |
| abstractText | 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 FcgammaRIII and its inhibitory receptor counterpart, FcgammaRIIB, 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 FcgammaRIIB and III abrogated the protective effect of IVIG on acute vaso-occlusive crisis caused by neutrophil recruitment and activation. Analysis of FcgammaRIIB- and FcgammaRIII-deficient mice revealed the predominant expression of FcgammaRIII on circulating neutrophils. FcgammaRIII mediated IVIG-triggered inhibition of leukocyte recruitment, circulating RBC capture, and enhanced Mac-1 activity, whereas FcgammaRIIB was dispensable. In addition, FcgammaRIII-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: FcgammaRIII, 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. |
