B cell-derived anti-beta 2 glycoprotein I antibody contributes to hyperhomocysteinaemia-aggravated abdominal aortic aneurysm.

Overactivated B cells secrete pathological antibodies, which in turn accelerate the formation of abdominal aortic aneurysms (AAAs). Hyperhomocysteinaemia (HHcy) aggravates AAA in mice; however, the underlying mechanisms remain largely elusive. In this study, we further investigated whether homocysteine (Hcy)-activated B cells produce antigen-specific antibodies that ultimately contribute to AAA formation. ELISA assays showed that HHcy induced the secretion of anti-beta 2 glycoprotein I (anti-β2GPI) antibody from B cells both in vitro and in vivo. Mechanistically, Hcy increased the accumulation of various lipid metabolites in B cells tested by liquid chromatography-tandem mass spectrometry, which contributed to elevated anti-β2GPI IgG secretion. By using the toll-like receptor 4 (TLR4)-specific inhibitor TAK-242 or TLR4-deficient macrophages, we found that culture supernatants from Hcy-activated B cells and HHcy plasma IgG polarized inflammatory macrophages in a TLR4-dependent manner. In addition, HHcy markedly increased the incidence of elastase- and CaPO4-induced AAA in male BALB/c mice, which was prevented in μMT mice. To further determine the importance of IgG in HHcy-aggravated AAA formation, we purified plasma IgG from HHcy or control mice and then transferred the IgG into μMT mice, which were subsequently subjected to elastase- or CaPO4-induced AAA. Compared with μMT mice that received plasma IgG from control mice, μMT mice that received HHcy plasma IgG developed significantly exacerbated elastase- or CaPO4-induced AAA accompanied by increased elastin degradation, MMP2/9 expression, and anti-β2GPI IgG deposition in vascular lesions, as shown by immunofluorescence histochemical staining. Our findings reveal a novel mechanism by which Hcy-induced B cell-derived pathogenic anti-β2GPI IgG might, at least in part, contribute to HHcy-aggravated chronic vascular inflammation and AAA formation.

Shao F ，Miao Y ，Zhang Y ，Han L ，Ma X ，Deng J ，Jiang C ，Kong W ，Xu Q ，Feng J ，Wang X ... -  《-》

Hyperhomocysteinemia exaggerates adventitial inflammation and angiotensin II-induced abdominal aortic aneurysm in mice.

Liu Z ，Luo H ，Zhang L ，Huang Y ，Liu B ，Ma K ，Feng J ，Xie J ，Zheng J ，Hu J ，Zhan S ，Zhu Y ，Xu Q ，Kong W ，Wang X ... -  《-》

Macrophage inflammasome mediates hyperhomocysteinemia-aggravated abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a serious vascular disease with high mortality. Our previous study suggested that hyperhomocysteinemia (HHcy) exaggerates the occurrence of AAA. Here, we investigated whether macrophage inflammasome is involved in HHcy-aggravated AAA formation. Two independent HHcy-aggravated AAA models, perivascular calcium phosphate-treated C57BL/6 mice and angiotensin II (Ang II)-infused apolipoprotein E-deficient (ApoE(-/-)) mice were used. NLPR3, caspase 1, and interleukin-1β (IL-1β) levels were higher in aneurysmal lesions of both HHcy models compared to controls, preferentially in macrophages. Similarly, macrophage inflammasome activation was observed in vitro. Folic acid administration reversed the HHcy-accelerated AAA, with ameliorated activation of inflammasome in the tunica adventitia. Lentiviral silencing of NLRP3 significantly ameliorated HHcy-aggravated AAA formation. We observed increased mitochondrial production of reactive oxygen species (ROS) and energy switch from oxidative phosphorylation to glycolysis with excess Hcy in macrophages. Blocking mitochondrial ROS production in macrophages abolished inflammasome activation. Our study highlights the potential importance of macrophage inflammasome in the pathogenesis and development of HHcy-aggravated AAA.

Sun W ，Pang Y ，Liu Z ，Sun L ，Liu B ，Xu M ，Dong Y ，Feng J ，Jiang C ，Kong W ，Wang X ... -  《-》

Peptide inhibitor of CXCL4-CCL5 heterodimer formation, MKEY, inhibits experimental aortic aneurysm initiation and progression.

Iida Y ，Xu B ，Xuan H ，Glover KJ ，Tanaka H ，Hu X ，Fujimura N ，Wang W ，Schultz JR ，Turner CR ，Dalman RL ... -  《-》

Fcγ receptor activation mediates vascular inflammation and abdominal aortic aneurysm development.

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 (FcγR) by immune complexes (IC) in the aortic wall contributes to AAA development. We therefore evaluated FcγR expression in AAA lesions and analysed whether inhibition of FcγR signaling molecules (γ-chain and Syk kinase) influences AAA formation in mice. FcγR 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 γ-chain knockout (γKO) mice (devoid of activating FcγR) in combination with macrophage adoptive transfer or Syk inhibitor treatment. To verify the mechanisms of FcγR in vitro, vascular smooth muscle cells (VSMC) and macrophages were stimulated with IgG IC. FcγR overexpression was detected in adventitia and media layers of human and mouse AAA. Elastase-perfused γKO 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 FcγR-expressing macrophages aggravated aneurysm in γKO mice. In vitro, FcγR 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. Our findings provide insight into the role and mechanisms mediating IgG-FcγR-associated inflammation and aortic wall injury in AAA, which might represent therapeutic targets against AAA disease.

Lopez-Sanz L ，Bernal S ，Jimenez-Castilla L ，Prieto I ，La Manna S ，Gomez-Lopez S ，Blanco-Colio LM ，Egido J ，Martin-Ventura JL ，Gomez-Guerrero C ... -  《Clinical and Translational Medicine》