Abstract 15497: Hematopoietic PI3-Kinase delta-Deficiency Causes Altered Macrophage and Regulatory T-cell Function and Aggravates Atherosclerosis in LDLR-/- Mice
Atherosclerosis and its consequences such as myocardial infarction and ischemic stroke remains the leading cause of death in western countries. During atherogenesis, arterial blood vessels become infiltrated by macrophages and T cells possessing inflammatory and regulatory functions. Leukocytes express the catalytic phosphoinositide 3-kinase isoform p110d (PI3Kd), exerting a key role in the regulation of immune responses including activation, differentiation and effector function. Therefore, PI3Kd represents a promising target for the modulation of inflammatory processes during atherogenesis.
To investigate the role of leukocytic PI3Kd during atherogenesis, lethally irradiated LDLR-/- mice were transplanted with bone marrow from PI3Kd-/- or PI3Kd+/+ mice and were fed an atherogenic diet for 6 weeks. Hypercholesterolemic PI3Kd-/- recipient LDLR-/- mice displayed a profound reduction of peripheral B and T cells as well as strongly impaired CD4+ T-cell activation, T-helper 1 response and regulatory T-cell numbers in paraaortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the profoundly impaired PI3Kd-deficient immune system caused a substantial aggravation of atherosclerosis in LDLR-/- mice. Atherosclerotic lesion area at the aortic root and whole aorta of PI3Kd-/- recipient LDLR-/- mice was significantly increased by 72% and 218% compared with PI3Kd+/+ recipients, respectively (n = 10-20; P < 0.001). Importantly, atherosclerotic lesions of PI3Kd-/- transplanted LDLR-/- mice were characterized by a lower fraction of CD4+ T cells and a higher proportion of macrophages compared with controls despite unaltered circulating monocyte subsets. Moreover, PI3Kd-deficient regulatory T cells and macrophages exhibited a strongly impaired suppressive capacity and an increased inflammatory polarization, respectively.
In summary, we demonstrate that hematopoietic PI3Kd plays a crucial role in regulating innate and adaptive immune responses within the arterial wall by exerting protective functions during atherogenesis. Current studies aim to dissect PI3Kd-dependent mechanisms that modulate inflammatory and regulatory processes in multiple stages of atherosclerosis.
Author Disclosures: M. Zierden: None. C. Millarg: None. M. Vantler: None. E.M. Berghausen: None. S. Baldus: None. S. Rosenkranz: Research Grant; Modest; United Therapeutics. Consultant/Advisory Board; Modest; United Therapeutics, Novartis, GSK, Pfizer. Research Grant; Significant; Actelion, Bayer, Novartis. Consultant/Advisory Board; Significant; Actelion, Bayer.
- © 2015 by American Heart Association, Inc.