Haematopoietic deficiency of the catalytic PI 3-kinase isoform PI3Kdelta aggravates the development of atherosclerosis in LDLR-/- mice

Abstract

Atherosclerosis is a chronic inflammatory disease of arterial blood vessels underlying myocardial infarction and ischaemic stroke. Atherogenesis is characterized by chronic infiltration of the arterial wall by macrophages, dendritic cells and T lymphocytes. Although different cell types of the innate and adaptive immune system play central pro-inflammatory roles, they exert regulatory functions in different stages of this complex disease as well. Leucocytes express the catalytic phosphoinositide 3-kinase isoform p110delta (PI3Kd), a key enzyme involved in the regulation of immune responses. Therefore, PI3Kd represents an interesting target for the modulation of atherogenesis. To investigate the role of PI3Kd in leucocytes for the orchestration of atherogen-esis, lethally irradiated LDLR-/- mice were either transplanted with bone marrow from PI3Kd-/- or PI3Kd+/+ mice. After 4 weeks of recovery, recipient mice were challenged for 6 weeks with atherogenic diet and successful reconstitution with donor bone marrow was verified by the representation of donor alleles in peripheral blood cells. PI3Kd-/- recipient LDLR-/- mice displayed a profound reduction of peripheral B and T cells as well as strongly impaired CD4+ T-cell activation and largely reduced numbers of regulatory T cells in the spleen and paraaor-tic lymph nodes compared with PI3Kd+/+ transplanted recipients. Surprisingly, the profound impairment of the immune system by PI3Kd-deficiency caused a considerable exacerbation of atherosclerosis in LDLR-/- mice. Atherosclerotic lesion area/aortic root area in PI3Kd-/- recipient LDLR-/- mice was significantly augmented compared with PI3Kd+/+ transplanted LDLR-/- mice (0, 35±0, 05 vs. 0, 27±0, 05; P<0.05), as shown by staining of proximal aortic sections with Oil Red O. Furthermore, lesion area/total aortic area in PI3Kd-/- recipients was also significantly higher than in PI3Kd+/+ transplanted LDLR-/- mice (0, 037±0, 007 vs. 0, 021±0, 007; P<0.05), as confirmed by en face analysis of Sudan IV-stained whole aortas. In summary, we demonstrate that haematopoietic PI3Kd plays a crucial role in regulating immune responses within the arterial wall by exerting protective functions during the development and progression of atherosclerosis. Current studies aim to dissect PI3Kd-dependent mechanisms that modulate inflammatory processes in multiple stages of atherosclerotic lesion formation.