PMID- 22415018
OWN - NLM
STAT- MEDLINE
DCOM- 20120529
LR  - 20220408
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 110
IP  - 8
DP  - 2012 Apr 13
TI  - Intravenous immunoglobulins modulate neutrophil activation and vascular injury 
      through FcgammaRIII and SHP-1.
PG  - 1057-66
LID - 10.1161/CIRCRESAHA.112.266411 [doi]
AB  - 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.
FAU - Jang, Jung-Eun
AU  - Jang JE
AD  - Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
FAU - Hidalgo, Andres
AU  - Hidalgo A
FAU - Frenette, Paul S
AU  - Frenette PS
LA  - eng
GR  - R01 HL069438/HL/NHLBI NIH HHS/United States
GR  - R01HL69438/HL/NHLBI NIH HHS/United States
GR  - R01 HL097700/HL/NHLBI NIH HHS/United States
GR  - R01HL097700/HL/NHLBI NIH HHS/United States
GR  - RC1HL099545/HL/NHLBI NIH HHS/United States
GR  - RC1 HL099545/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Video-Audio Media
DEP - 20120313
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Fcgr2b protein, mouse)
RN  - 0 (Fcgr3 protein, mouse)
RN  - 0 (Immunoglobulins, Intravenous)
RN  - 0 (Macrophage-1 Antigen)
RN  - 0 (Receptors, IgG)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6)
RN  - EC 3.1.3.48 (Ptpn6 protein, mouse)
SB  - IM
MH  - Anemia, Sickle Cell/*drug therapy/enzymology/genetics/immunology/pathology
MH  - Animals
MH  - Constriction, Pathologic
MH  - Endothelial Cells/*drug effects/enzymology/immunology/pathology
MH  - Erythrocytes/drug effects/metabolism
MH  - Immunoglobulins, Intravenous/*pharmacology
MH  - Macrophage-1 Antigen/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microscopy, Video
MH  - Muscle, Smooth/*blood supply
MH  - Neutrophil Activation/*drug effects
MH  - Neutrophils/*drug effects/enzymology/immunology
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 6/*metabolism
MH  - Receptors, IgG/deficiency/genetics/*metabolism
MH  - Time Factors
MH  - Vascular Diseases/enzymology/genetics/immunology/pathology/*prevention & control
MH  - Venules/drug effects/enzymology/immunology
PMC - PMC3351009
MID - NIHMS369074
EDAT- 2012/03/15 06:00
MHDA- 2012/05/30 06:00
PMCR- 2013/04/13
CRDT- 2012/03/15 06:00
PHST- 2012/03/15 06:00 [entrez]
PHST- 2012/03/15 06:00 [pubmed]
PHST- 2012/05/30 06:00 [medline]
PHST- 2013/04/13 00:00 [pmc-release]
AID - CIRCRESAHA.112.266411 [pii]
AID - 10.1161/CIRCRESAHA.112.266411 [doi]
PST - ppublish
SO  - Circ Res. 2012 Apr 13;110(8):1057-66. doi: 10.1161/CIRCRESAHA.112.266411. Epub 
      2012 Mar 13.