Macrophage scavenger receptor A1 antagonizes abdominal aortic aneurysm via upregulating IRG1

Abstract

Aims: Abdominal aortic aneurysm (AAA) is a common, usually asymptomatic disease with high mortality and limited therapeutic options. Extensive extracellular matrix (ECM) fragmentation and transmural inflammation act as major pathological processes of AAA. However, the underlying regulatory mechanisms remain incompletely understood. Herein, we aimed to investigate the role of scavenger receptor A1 (SR-A1), a key pattern recognition receptor modulating macrophage activity, in pathogenesis of AAA.

Methods and results: The AAA model was generated by administration of angiotensin II (Ang II) into apolipoprotein E knockout mice or peri-arterial application of calcium phosphate in C57BJ/6L mice. We found that SR-A1 was markedly down-regulated in the macrophages isolated from murine AAA aortas. Global or myeloid-specific ablation of SR-A1 aggravated vascular inflammation, loss of vascular smooth muscle cells and degradation of the extracellular matrix. These effects of SR-A1 deficiency on AAA development were mediated by suppressed immunoresponsive gene 1 (IRG1) and increased inflammatory response in macrophages. Mechanically, binding of SR-A1 with Lyn led to STAT3 phosphorylation and translocation into the nucleus, in which STAT3 promoted IRG1 transcription through directly binding to its promoter. Restoration of macrophage SR-A1 in SR-A1-deficient mice by bone marrow transplantation or administration of 4-octyl itaconate, the derivate of IRG1 product itaconate, could relieve murine AAA.

Conclusion: Our study reveals a protective effect of macrophage SR-A1-STAT3-IRG1 axis against aortic aneurysm formation via inhibiting inflammation.

Keywords: 4-OI, 4-octyl itaconate (PubChem CID: 14239884); Abdominal aortic aneurysm; Colivelin (PubChem CID: 90477169); Immunoresponsive gene 1; Inflammation; Macrophage; Scavenger receptor A1; cryptotanshinone (PubChem CID: 160254).