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

Abstract

BackgroundRecruitment of macrophage precursors to the adventitia plays a key role in the pathogenesis of abdominal aortic aneurysms (AAAs), but molecular mechanisms remain undefined. The innate immune signaling molecule CD14 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 CD14 plays a crucial role in adventitial macrophage precursor recruitment early during AAA formation.Methods and ResultsCD14−/− mice were resistant to AAA formation induced by 2 different AAA induction models: aortic elastase infusion and systemic angiotensin II (AngII) infusion. CD14 gene deletion led to reduced aortic macrophage infiltration and diminished elastin degradation. Adventitial monocyte binding to AngII‐infused aorta in vitro was dependent on CD14, 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 CD14 expression. Conditioned medium from AoAf and PVAT induced CD14‐dependent monocyte chemotaxis, which was potentiated by IL‐6. CD14 expression in aorta and plasma CD14 levels were increased in AAA patients compared with controls.ConclusionsThese findings link CD14 innate immune signaling via a novel IL‐6 amplification loop to adventitial macrophage precursor recruitment in the pathogenesis of AAA.

The role of perivascular adipose tissue in vasoconstriction, arterial stiffness, and aneurysm

“…Significantly, patients with an abdominal aortic aneurysm showed increased CD14 in the aorta, whereas CD14-deficient mice were resistant to aneurysmal formation. In addition, IL-6 potentiated the up-regulation of CD14 expression and CD14-dependent chemotaxis in human THP-1 monocytes treated with conditioned medium from PVAT, suggesting that PVAT-derived proinflammatory factors might promote active macrophage infiltration to induce aneurysmal development [78]. These results support the observation that higher thoracic and abdominal aortic dimensions were associated with PVAT volume in the Framingham Offspring and Third Generation cohorts [70].…”

“…PVAT plays a critical role in the recruitment of immune cells into the adventitia layer of the vascular wall. T cells and macrophage infiltration in PVAT has been observed in experimental models of hypertension including angiotensin II (Ang II) or endothelin-1 preceding observable pathological vascular dysfunction such as atherosclerosis, arterial stiffness, or aneurysm [78, 79]. Upon the development of hypertension, significant changes of adipokine expression profile are observed in the PVAT.…”

Characterization of a Resident Population of Adventitial Macrophage Progenitor Cells in Postnatal Vasculature

“…This fits with the proliferative, clonogenic nature of Sca-1 + CD45 + AMPCs, which are located to be able to contribute to the presence of MPS populations found in the adventitia of healthy arteries, 16 as well as the rapid expansion of adventitial macrophages that occurs during the development of atherosclerosis and aneurysms, where these cells also help regulate growth of pathogenic vasa vasorum. 2,26,27 We are currently focusing on the proangiogenic properties of Sca-1 + CD45 + AMPCs, which we hypothesize may underlie one of their major pathophysiological functions during arterial wall remodeling. Although our results indicate that adventitial progenitors may contribute to only a small proportion of neointimal leukocytes, alternative model systems, such as molecular fate-mapping and arterial graft interposition, will be required before definitively excluding a greater role for AMPCs as a source of locally maintained macrophages in atheroma.…”

Vascular Wall Progenitor Cells in Health and Disease

“…122,125 It provides an interface connecting the rest of the vessel wall to the highly cellular and cytokinerich perivascular adipose and connective tissue, as well as the peripheral circulation by virtue of its content of thin-walled microvessels. Thus, it is well situated to serve as an injury sensor for the rest of the vessel wall, and this is reflected by its early activation in different vascular disease models, such as atherosclerosis, 11 ligation and balloon injury, 126 aneurysm formation, 127 and pulmonary hypertension. 125 Manifestations of adventitial activation include increased cell proliferation, upregulation of extracellular matrix, matricellular, contractile + multipotent stem cells (MPSCs) in humans.…”