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Coupling of Fc? receptor I to Fc? receptor IIb by SRC kinase mediates C-reactive protein impairment of endothelial function.

ABSTRACT: Elevations in C-reactive protein (CRP) are associated with increased cardiovascular disease risk and endothelial dysfunction. CRP antagonizes endothelial nitric oxide synthase (eNOS) through processes mediated by the IgG receptor Fc? receptor IIB (Fc?RIIB), its immunoreceptor tyrosine-based inhibitory motif, and SH2 domain-containing inositol 5'-phosphatase 1. In mice, CRP actions on eNOS blunt carotid artery re-endothelialization.How CRP activates Fc?RIIB in endothelium is not known. We determined the role of Fc? receptor I (Fc?RI) and the basis for coupling of Fc?RI to Fc?RIIB in endothelium.In cultured endothelial cells, Fc?RI-blocking antibodies prevented CRP antagonism of eNOS, and CRP activated Src via Fc?RI. CRP-induced increases in Fc?RIIB immunoreceptor tyrosine-based inhibitory motif phosphorylation and SH2 domain-containing inositol 5'-phosphatase 1 activation were Src-dependent, and Src inhibition prevented eNOS antagonism by CRP. Similar processes mediated eNOS antagonism by aggregated IgG used to mimic immune complex. Carotid artery re-endothelialization was evaluated in offspring from crosses of CRP transgenic mice (TG-CRP) with either mice lacking the ? subunit of Fc?RI (FcR?(-/-)) or Fc?RIIB(-/-) mice. Whereas re-endothelialization was impaired in TG-CRP vs wild-type, it was normal in both FcR?(-/-); TG-CRP and Fc?RIIB(-/-); TG-CRP mice.CRP antagonism of eNOS is mediated by the coupling of Fc?RI to Fc?RIIB by Src kinase and resulting activation of SH2 domain-containing inositol 5'-phosphatase 1, and consistent with this mechanism, both Fc?RI and Fc?RIIB are required for CRP to blunt endothelial repair in vivo. Similar mechanisms underlie eNOS antagonism by immune complex. Fc?RI and Fc?RIIB may be novel therapeutic targets for preventing endothelial dysfunction in inflammatory or immune complex-mediated conditions.

SUBMITTER: Sundgren NC

PROVIDER: S-EPMC3215097 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Coupling of Fcγ receptor I to Fcγ receptor IIb by SRC kinase mediates C-reactive protein impairment of endothelial function.

Sundgren Nathan C NC Zhu Weifei W Yuhanna Ivan S IS Chambliss Ken L KL Ahmed Mohamed M Tanigaki Keiji K Umetani Michihisa M Mineo Chieko C Shaul Philip W PW

Circulation research 20110922 10

<h4>Rationale</h4>Elevations in C-reactive protein (CRP) are associated with increased cardiovascular disease risk and endothelial dysfunction. CRP antagonizes endothelial nitric oxide synthase (eNOS) through processes mediated by the IgG receptor Fcγ receptor IIB (FcγRIIB), its immunoreceptor tyrosine-based inhibitory motif, and SH2 domain-containing inositol 5'-phosphatase 1. In mice, CRP actions on eNOS blunt carotid artery re-endothelialization.<h4>Objective</h4>How CRP activates FcγRIIB in ...[more]

PMID: 21940940

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Project description:Epidermolysis bullosa acquisita (EBA) is an autoimmune skin blistering disease characterized by IgG autoantibodies (aAb) against type VII collagen (COL7). The mechanisms controlling the formation of such aAbs and their effector functions in the skin tissue are incompletely understood. Here, we assessed whether the inhibitory IgG Fc receptor, Fc?RIIB, controls the development of autoimmune skin blistering disease in an active model of EBA. For this purpose, we immunized congenic EBA-susceptible B6.SJL-H2s (B6.s) and B6.s-Fcgr2b -/- mice with the immunodominant vWFA2 region of COL7. B6.s-Fcgr2b -/- mice developed a strong clinical phenotype with 15 ± 3.3% of affected body surface area at week 4. In contrast, the body surface area in B6.s mice was affected to a maximum of 5% at week 6 with almost no disease signs at week 4. Surprisingly, we already found strong but similar COL7-specific serum IgG1 and IgG2b aAb production at week 2. Further, aAb and C3b deposition in the skin of B6.s and B6.s-Fcgr2b -/- mice increased between weeks 2 and 6 after vWFA2 immunization. Importantly, neutrophil skin infiltration and activation was much stronger in B6s-Fcgr2b -/- than in B6.s mice and already present at week 2. Also, the early aAb response in B6.s-Fcgr2b -/- mice was more diverse than in wt B6.s mice. Reactive oxygen species (ROS) release from infiltrating neutrophils play a crucial role as mediator of skin inflammation in EBA. In line, sera from B6.s and B6.s-Fcgr2b -/- mice induced strong ROS release from bone marrow-neutrophils in vitro. In contrast to the antibody-transfer-induced EBA model, individual targeting of Fc?RIII or Fc?RIV decreased ROS release to 50%. Combined Fc?R blocking abrogated ROS release from BM neutrophils. Also, ROS release induced by COL7-specific serum IgG aAbs was significantly higher using BM neutrophils from B6.s-Fcgr2b -/- than from B6.s mice. Together, our findings identified Fc?RIIB as a suppressor of skin inflammation in the active EBA model through inhibition of early epitope spreading, protection from strong early neutrophil infiltration to and activation of neutrophils in the skin and suppression of Fc?RIII activation by IgG1 aAbs which drive strong ROS release from neutrophils leading to tissue destruction at the dermal-epidermal junction.

Dataset Information

Coupling of Fc? receptor I to Fc? receptor IIb by SRC kinase mediates C-reactive protein impairment of endothelial function.

Publications

Coupling of Fcγ receptor I to Fcγ receptor IIb by SRC kinase mediates C-reactive protein impairment of endothelial function.

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