Depletion of CD11c+ dendritic cells in apolipoprotein E-deficient mice limits angiotensin II-induced abdominal aortic aneurysm formation and growth

Abstract

Objective: The role of chronic inflammation in abdominal aortic aneurysm (AAA) is controversial. CD11c+ antigen-presenting cells (APCs) (dendritic cells (DCs)) have been reported in human AAA samples but their role is unclear. The effect of conditional depletion of CD11c+ cells on experimental AAA was investigated in the angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE–/–) mouse model. Approach: CD11c-diphtheria toxin (DT or D.tox) receptor (DTR), ovalbumin (OVA) fragment aa 140–386, and enhanced green fluorescent protein (eGFP)-ApoE–/– (CD11c.DOG.ApoE–/–) mice were generated and CD11c+ cell depletion achieved with D.tox injections (8 ng/g body weight, i.p., every-other-day). AAA formation and growth were assessed by measurement of supra-renal aortic (SRA) diameter in vivo by serial ultrasound and by morphometry assessment of harvested aortas at the end of the study. Results: Depletion of CD11c+ cells by administration of D.tox on alternative days was shown to reduce the maximum diameter of AAAs induced by 28 days AngII infusion compared with controls (D.tox, 1.58 ± 0.03 mm vs Vehicle control, 1.81 ± 0.06 mm, P<0.001). CD11c+ depletion commencing after AAA establishment by 14 days of AngII infusion, was also shown to lead to smaller AAAs than controls after a further 14 days (D.tox, 1.54 ± 0.04 mm vs Vehicle control, 1.80 ± 0.03 mm, P<0.001). Flow cytometry revealed significantly lower numbers of circulating CD44hi CD62Llo effector CD4 T cells, CD44hi CD62Llo effector CD8 T cells and B220+ B cells in CD11c+ cell-depleted mice versus controls. CD11c+ depletion attenuated SRA matrix degradation indicated by decreased neutrophil elastase activity (P=0.014), lower elastin degradation score (P=0.012) and higher collagen content (P=0.002). Conclusion: CD11c+ cell-depletion inhibited experimental AAA development and growth associated with down-regulation of circulating effector T cells and attenuated matrix degradation. The findings suggest involvement of autoreactive immune cells in AAA pathogenesis.

CD248+CD8+ T lymphocytes suppress pathological vascular remodeling in human thoracic aortic aneurysms

“…Vascular inflammatory reactions seem to play a pivotal role in the development and progression of aortic aneurysms. 17 In the aortic tissues of patients with TAA, here we found that aortic CD248 was significantly increased mainly by the CD8+ T cells (CD248+CD8+) infiltrating the adventitia and media of aortic aneurysms. Interestingly, the recruitment of CD248+CD8+ T cells in situ was coincident with the reduced circulating CD248+CD8+ T cell subpopulation in patients with TAA when compared with patients with CAD and healthy subjects, strongly indicating that CD248 may participate in pathological vascular remodeling via infiltrating CD8+ T cell-involved vascular inflammatory response, particularly in patients with TAA.…”

“…Given the previous studies showing that CD248 is closely linked to microvasculature maturation, 17 we reasoned that CD248 is also involved in pathological accumulation of microvessels in the adventitia and media of aortic aneurysms. We next examined the changes of CD248 expression in aortic walls of patients with TAA.…”

Profiles of immune infiltration in abdominal aortic aneurysm and their associated marker genes: a gene expression-based study

“…Among innate immune cells in AAA patients, infiltrating NK cells can produce a high level of pro-inflammatory cytokines and perforin that might cause or exacerbate aortic tissue damage and increase the cytotoxicity against aortic SMCs ( 22 ). Dendritic cells are the most potent antigen-presenting cells that come in contact with T cells within lymphoid follicles and have a role in regulating the functional activity of immune response in AAA ( 23 ). Neutrophils appear to be one of the early contributors in AAA formation through secreting some specific ECM-degrading enzymes and neutrophil protease ( 3 , 24 ).…”

Abdominal Aortic Aneurysm: Roles of Inflammatory Cells

“…Dendritic cells (DCs) are a kind of antigen presenting cells (APC) which are able to process and expose antigen components to T lymphocytes, play a key role in the induction of innate immune responses and are implicated in the immune tolerance to self-antigens ( 40 , 41 ). Krishna et al.…”

“…Krishna et al. indicated that depletion of CD11c + cells can significantly decrease the maximum diameter of AAAs 28 days after angiotensin II infusion ( 40 ), which suggests that DCs may also have important impact on the development of AAA.…”