Abstract 15489: Hematopoietic PI3-Kinase δ-Deficiency Exacerbates Lesional Macrophage Infiltration and Atherosclerosis in LDLR-/- Mice

Abstract

Atherosclerosis and its consequences such as myocardial infarction and ischemic stroke remains the leading cause of death in western countries. Atherosclerosis is a chronic inflammatory disease of arterial blood vessels, critically involving macrophages, dendritic cells and T lymphocytes. Leukocytes highly express the catalytic phosphoinositide 3-kinase isoform p110δ (PI3Kδ), exerting a key role in the regulation of immune responses including activation, differentiation and effector function of lymphocytes. Therefore, PI3Kδ represents a promising target for the modulation of inflammatory processes during atherogenesis. To investigate the role of leukocytic PI3Kδ during atherogenesis, lethally irradiated LDLR -/- mice were either transplanted with bone marrow from PI3Kδ -/- or PI3Kδ +/+ mice. After recovery, recipient mice were fed an atherogenic diet for 6 weeks. Hypercholesterolemic PI3Kδ -/- 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 PI3Kδ +/+ transplanted controls. Surprisingly, the profound impairment of the adaptive immune system by PI3Kδ-deficiency caused a considerable aggravation of atherosclerosis in LDLR -/- mice. Atherosclerotic lesion area at the aortic root and abdominal aorta of PI3Kδ -/- recipient LDLR -/- mice was significantly increased by 72% and 218% compared with PI3Kδ +/+ recipients, respectively (n = 10[[Unable to Display Character: –]]20; P < 0.001). Importantly, atherosclerotic lesions of PI3Kδ-deficient LDLR -/- mice were characterized by a lower fraction of CD4 + T cells and a higher proportion of MOMA-2 + monocytes/macrophages compared with controls despite unaltered circulating monocyte subsets. Thus, PI3Kδ-deficiency in mononuclear phagocytes may contribute to enhanced plaque growth. In summary, we demonstrate that hematopoietic PI3Kδ 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 PI3Kδ-dependent mechanisms that modulate inflammatory and regulatory processes in multiple stages of atherosclerosis.