Fcγ receptor activation mediates vascular inflammation and abdominal aortic aneurysm development

Background Abdominal aortic aneurysm (AAA), a degenerative vascular pathology characterized by permanent dilation of the aorta, is considered a chronic inflammatory disease involving innate/adaptive immunity. However, the functional role of antibody-dependent immune response against antigens present in the damaged vessel remains unresolved. We hypothesized that engagement of immunoglobulin G (IgG) Fc receptors (Fc gamma R) by immune complexes (IC) in the aortic wall contributes to AAA development. We therefore evaluated Fc gamma R expression in AAA lesions and analysed whether inhibition of Fc gamma R signaling molecules (gamma-chain and Syk kinase) influences AAA formation in mice. Methods Fc gamma R gene/protein expression was assessed in human and mouse AAA tissues. Experimental AAA was induced by aortic elastase perfusion in wild-type (WT) mice and gamma-chain knockout (gamma KO) mice (devoid of activating Fc gamma R) in combination with macrophage adoptive transfer or Syk inhibitor treatment. To verify the mechanisms of Fc gamma R in vitro, vascular smooth muscle cells (VSMC) and macrophages were stimulated with IgG IC. Results Fc gamma R overexpression was detected in adventitia and media layers of human and mouse AAA. Elastase-perfused gamma KO mice exhibited a decrease in AAA incidence, aortic dilation, elastin degradation, and VSMC loss. This was associated with (1) reduced infiltrating leukocytes and immune deposits in AAA lesions, (2) inflammatory genes and metalloproteinases downregulation, (3) redox balance restoration, and (4) converse phenotype of anti-inflammatory macrophage M2 and contractile VSMC. Adoptive transfer of Fc gamma R-expressing macrophages aggravated aneurysm in gamma KO mice. In vitro, Fc gamma R deficiency attenuated inflammatory gene expression, oxidative stress, and phenotypic switch triggered by IC. Additionally, Syk inhibition prevented IC-mediated cell responses, reduced inflammation, and mitigated AAA formation. Conclusion Our findings provide insight into the role and mechanisms mediating IgG-Fc gamma R-associated inflammation and aortic wall injury in AAA, which might represent therapeutic targets against AAA disease.

Automated summary

Research has shown that overexpression of FcγR has been detected in abdominal aortic aneurysm lesions, and inhibiting FcγR signaling molecules can reduce AAA development, restore inflammatory responses and vascular wall injury, potentially serving as therapeutic targets for AAA disease.