CD14 Directs Adventitial Macrophage Precursor Recruitment: Role in Early Abdominal Aortic Aneurysm Formation

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Abstract
Background: Recruitment of macrophage precursors to the adventitia plays a key role in the pathogenesis of abdominal aortic aneurysms ( AAA s), but molecular mechanisms remain undefined. The innate immune signaling molecule CD 14 was reported to be upregulated in adventitial macrophages in a murine model of AAA and in monocytes cocultured with aortic adventitial fibroblasts (AoAf) in vitro , concurrent with increased interleukin‐6 (IL‐6) expression. We hypothesized that CD 14 plays a crucial role in adventitial macrophage precursor recruitment early during AAA formation. Methods and Results: CD 14 −/− mice were resistant to AAA formation induced by 2 different AAA induction models: aortic elastase infusion and systemic angiotensin II (Ang II ) infusion. CD 14 gene deletion led to reduced aortic macrophage infiltration and diminished elastin degradation. Adventitial monocyte binding to Ang II ‐infused aorta in vitro was dependent on CD 14, and incubation of human acute monocytic leukemia cell line‐1 (THP‐1) monocytes with IL ‐6 or conditioned medium from perivascular adipose tissue ( PVAT ) upregulated CD 14 expression. Conditioned medium from AoAf and PVAT induced CD 14‐dependent monocyte chemotaxis, which was potentiated by IL ‐6. CD 14 expression in aorta and plasma CD 14 levels were increased in AAA patients compared with controls. Conclusions: These findings link CD 14 innate immune signaling via a novel IL ‐6 amplification loop to adventitial macrophage precursor recruitment in the pathogenesis of AAA .

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