title: Intravenous immunoglobulins modulate neutrophil activation and vascular injury through FcγRIII and SHP-1.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  We examined neutrophil behavior in response to IVIG in vivo, using real-time intravital microscopy. We found that an antibody that blocks both FcγRIII and its inhibitory receptor counterpart, FcγRIIB, 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 FcγRIIB and III abrogated the protective effect of IVIG on acute vaso-occlusive crisis caused by neutrophil recruitment and activation. Analysis of FcγRIIB- and FcγRIII-deficient mice revealed the predominant expression of FcγRIII on circulating neutrophils. FcγRIII mediated IVIG-triggered inhibition of leukocyte recruitment, circulating RBC capture, and enhanced Mac-1 activity, whereas FcγRIIB was dispensable. In addition, FcγRIII-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
  FcγRIII, 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.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Jang
authors.forename: Andrés
authors.initials: A
authors.lastname: Hidalgo
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D003251:Constriction, Pathologic; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018715:Microscopy, Video; D009130:Muscle, Smooth / Q000098:blood supply*; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014652:Vascular Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014699:Venules / Q000187:drug effects / Q000201:enzymology / Q000276:immunology
chemical_list: C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; D016756:Immunoglobulins, Intravenous; D016177:Macrophage-1 Antigen; D017452:Receptors, IgG; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse