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??T cells are prevalent in the proximal aorta and drive nascent atherosclerotic lesion progression and neutrophilia in hypercholesterolemic mice.

ABSTRACT: Unique innate immunity-linked ??T cells have been seen in early human artery lesions, but their role in lesion development has received little attention. Here we investigated whether ??T cells modulate atherogenesis in apolipoprotein E-deficient (ApoE KO) mice. We found that ??T cell numbers were markedly increased in the proximal aorta of ApoE-deficient vs. wild-type mice during early atherogenesis, particularly in the aortic root and arch, where they comprised most of the T cells and lesion progression is most rapid. ??T cells infiltrated intimal lesions in ApoE KO mice, but only the adventitia in wild-type mice, and were more prevalent than CD4+ T cells in early nascent lesions, as evaluated by en face confocal microscopy. These aortic ??T cells produced IL-17, but not IFN-?, analyzed by ex vivo FACS. Furthermore, aortic arch lipid accumulation correlated strongly with abundance of IL-17-expressing splenic ??T cells in individual ApoE KO mice. To investigate the role of these ??T cells in early atherogenesis, we analyzed ApoE/??T double knockout (DKO) compared to ApoE KO mice. We observed reduced early intimal lipid accumulation at sites of nascent lesion formation, both in chow-fed (by 40%) and Western diet-fed (by 44%) ApoE/??T DKO mice. In addition, circulating neutrophils were drastically reduced in these DKO mice on Western diet, while expansion of inflammatory monocytes and splenic Th1 or Th17 lymphocytes was not affected. These data reveal, for the first time, a pathogenic role of ??T cells in early atherogenesis in ApoE KO mice, by mechanisms likely to involve their IL-17 production and induction of neutrophilia. Targeting ??T cells thus might offer therapeutic benefit in atherosclerosis or other inflammatory vascular diseases.

SUBMITTER: Vu DM

PROVIDER: S-EPMC4196850 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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γδT cells are prevalent in the proximal aorta and drive nascent atherosclerotic lesion progression and neutrophilia in hypercholesterolemic mice.

Vu Duc M DM Tai Albert A Tatro Jeffrey B JB Karas Richard H RH Huber Brigitte T BT Beasley Debbie D

PloS one 20141014 10

Unique innate immunity-linked γδT cells have been seen in early human artery lesions, but their role in lesion development has received little attention. Here we investigated whether γδT cells modulate atherogenesis in apolipoprotein E-deficient (ApoE KO) mice. We found that γδT cell numbers were markedly increased in the proximal aorta of ApoE-deficient vs. wild-type mice during early atherogenesis, particularly in the aortic root and arch, where they comprised most of the T cells and lesion pr ...[more]

PMID: 25313857

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Project description:Background Penetrating ulcers of aorta, aortic dissections and intramural hematomas all come under acute aortic syndromes and have important similarities and differences. Case report We report a 67?year old man with rupture of a large penetrating ulcer of the distal ascending aorta with hemopericardium and left hemothorax. He underwent interposition graft replacement of ascending aorta and hemi-arch with a 30?mm Gelweave Vascutek graft but represented 6?months later with development of a penetrating ulcer which ruptured into a huge 14?cm pseudoaneurysm. This was repaired with a 28?mm Vascutek Gelseal graft replacement of arch and interposition graft reconstruction of innominate and left common carotid arteries. 6?weeks later, however, he ruptured his proximal descending aorta and underwent TEVAR satisfactorily. Unfortunately, 2?days later, he developed a pathological fracture of left proximal tibia with metastasis from a primary renal cell carcinoma. He died 3?weeks later from respiratory failure. We shall briefly outline the similarities and differences in presentation and management of penetrating aortic ulcers, aortic dissections and intramural haematomas. We shall discuss, in greater detail, penetrating ulcers of thoracic aorta, their natural history, location, complications and management. Conclusion This case report is unique on account of initial successful surgical redressal following rupture of penetrating ulcer of distal ascending aorta into left pleural and pericardial cavities, normally associated with instant death. The haemodynamic effects of the rupture were staggered due to initial contained rupture into a smaller pseudoaneurysm, followed by a further rupture into a false aneurysmal sac followed eventually by generalised rupture into the pleural and pericardial cavities - a unique way of aortic rupture. Further development of another penetrating ulcer and a small pseudoaneurysm in the distal arch 6?months later which further ruptured into a larger 14?cm false aneurysmal sac, which again did not result in exsanguination, is again extraordinarily rare. Thereafter he underwent emergency thoracic endovascular aortic repair (TEVAR) for a further rupture of descending thoracic aorta. All three ruptures were managed successfully and would usually be associated with near-certain death, only for the patient to succumb eventually to the complications of metastatic renal cell carcinoma.

Project description:Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes atherosclerosis by increasing low-density lipoprotein (LDL) cholesterol levels through degradation of hepatic LDL receptor (LDLR). Studies have described the systemic effects of PCSK9 on atherosclerosis, but whether PCSK9 has local and direct effects on the plaque is unknown. To study the local effect of human PCSK9 (hPCSK9) on atherosclerotic lesion composition, independently of changes in serum cholesterol levels, we generated chimeric mice expressing hPCSK9 exclusively from macrophages, using marrow from hPCSK9 transgenic (hPCSK9tg) mice transplanted into apoE(-/-) and LDLR(-/-) mice, which were then placed on a high-fat diet (HFD) for 8 weeks. We further characterized the effect of hPCSK9 expression on the inflammatory responses in the spleen and by mouse peritoneal macrophages (MPM) in vitro. We found that MPMs from transgenic mice express both murine (m) Pcsk9 and hPCSK9 and that the latter reduces macrophage LDLR and LRP1 surface levels. We detected hPCSK9 in the serum of mice transplanted with hPCSK9tg marrow, but did not influence lipid levels or atherosclerotic lesion size. However, marrow-derived PCSK9 progressively accumulated in lesions of apoE(-/-) recipient mice, while increasing the infiltration of Ly6C(hi) inflammatory monocytes by 32% compared with controls. Expression of hPCSK9 also increased CD11b- and Ly6C(hi) -positive cell numbers in spleens of apoE(-/-) mice. In vitro, expression of hPCSK9 in LPS-stimulated macrophages increased mRNA levels of the pro-inflammatory markers Tnf and Il1b (40% and 45%, respectively) and suppressed those of the anti-inflammatory markers Il10 and Arg1 (30% and 44%, respectively). All PCSK9 effects were LDLR-dependent, as PCSK9 protein was not detected in lesions of LDLR(-/-) recipient mice and did not affect macrophage or splenocyte inflammation. In conclusion, PCSK9 directly increases atherosclerotic lesion inflammation in an LDLR-dependent but cholesterol-independent mechanism, suggesting that therapeutic PCSK9 inhibition may have vascular benefits secondary to LDL reduction.

Dataset Information

??T cells are prevalent in the proximal aorta and drive nascent atherosclerotic lesion progression and neutrophilia in hypercholesterolemic mice.

Publications

γδT cells are prevalent in the proximal aorta and drive nascent atherosclerotic lesion progression and neutrophilia in hypercholesterolemic mice.

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