Intravenous immunoglobulins modulate neutrophil activation and vascular injury through fcγRIII and SHP-1

Jung Eun Jang, Andrés Hidalgo, Paul S. Frenette

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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 FcγRIIIB 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.

Original languageEnglish (US)
Pages (from-to)1057-1066
Number of pages10
JournalCirculation Research
Volume110
Issue number8
DOIs
StatePublished - Apr 13 2012

Fingerprint

Neutrophil Activation
Vascular System Injuries
Intravenous Immunoglobulins
Phosphoric Monoester Hydrolases
Tyrosine
Neutrophils
Neutrophil Infiltration
Leukocytes
Erythrocytes
Sickle Cell Anemia
Cell Communication
Anti-Inflammatory Agents

Keywords

  • adhesion molecules
  • endothelial cells
  • Fc
  • inflammation
  • intravenous immunoglobulin
  • neutrophils
  • RIII
  • Src homology 2-containing tyrosine phosphatase-1
  • vascular injury

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Intravenous immunoglobulins modulate neutrophil activation and vascular injury through fcγRIII and SHP-1. / Jang, Jung Eun; Hidalgo, Andrés; Frenette, Paul S.

In: Circulation Research, Vol. 110, No. 8, 13.04.2012, p. 1057-1066.

Research output: Contribution to journalArticle

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