Introduction and purpose Atherosclerosis is a chronic inflammatory disease of arteries, critically involving leukocytes like macrophages as well as T and B lymphocytes. Macrophages are major drivers of disease through the ingestion of lipoproteins, foam cell formation, and secretion of inflammatory mediators. Although macrophages outnumber other leukocytes in atherosclerotic plaques, T and B cells can shape the course of disease by promoting or mitigating inflammatory responses. Leukocytes highly express the phosphoinositide 3-kinase isoform delta (PI3Kd), exerting a key role in the regulation of immune responses including activation, proliferation, differentiation, and effector functions. Therefore, PI3Kd represents a promising target for the modulation of inflammatory diseases. Consequently, we aimed to analyse the role of PI3Kd in leukocytes during atherogenesis. Methods and results To investigate the role of PI3Kd in atherosclerosis, bone marrow from PI3Kd−/− or PI3Kd+/+ mice was transplanted into LDLR−/− mice. After a 6-weeks-challenge by high fat diet, PI3Kd−/− recipient LDLR−/− mice displayed profoundly impaired CD4+ and CD8+ T-cell numbers, CD4+ T-cell activation, CD4+ effector T-cell differentiation, and proatherogenic CD4+ T-helper (Th) 1 responses in para-aortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the net effect of PI3Kd deficiency was a substantial increase of aortic inflammation and atherosclerosis in LDLR−/− mice. Whereas plaque content and functions of macrophages including foam cell formation, efferocytosis, and cytokine secretion remained unaffected, haematopoietic PI3Kd ablation strongly reduced mature B cells and serum immunoglobulins in LDLR−/− mice. Importantly, PI3Kd deficiency severely impaired numbers and immunosuppressive functions of regulatory CD4+ T cells (Tregs) in spleen, para-aortic lymph nodes, and plaques of LDLR−/− mice. Consequently, adoptive transfer of PI3Kd+/+ Tregs fully constrained the plaque burden in PI3Kd−/− transplanted LDLR−/− mice without affecting B-cell numbers and serum immunoglobulins, whereas adoptively transferred PI3Kd−/− Tregs were unable to relieve atherosclerosis progression. Conclusions Here, we demonstrate that PI3Kd plays a crucial role in Tregs, Th1 cells, and B cells during atherogenesis. Lack of PI3Kd signalling specifically in atheroprotective Treg responses outplays its impact on proatherogenic Th1 and B-cell responses, thus leading to aggravated atherosclerosis. Hence, PI3Kd is a key regulator of Treg biology and thereby protects against atherosclerosis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Marga and Walter Boll Foundation
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.
Introduction and purpose Atherosclerosis is a chronic inflammatory disease of arteries and represents the main underlying cause of death worldwide. Macrophages are major drivers of atherosclerosis by ingestion of lipoproteins, foam cell formation, and secretion of pro-inflammatory mediators. Although macrophages outnumber other leukocytes in atherosclerotic plaques, T and B lymphocytes can shape the course of disease by promoting or mitigating inflammatory responses. Leukocytes highly express the phosphoinositide 3-kinase isoform delta (PI3Kd), exerting a key role in the regulation of immune responses including the activation, proliferation, differentiation, and effector function of lymphocytes. Since macrophages and lymphocytes are all major effectors of atherosclerosis, we aimed to understand the role of PI3Kd in these leukocytes during atherogenesis. Methods and results To investigate the role of haematopoietic PI3Kd in atherosclerosis, bone marrow from PI3Kd−/− or PI3Kd+/+ mice was transplanted into LDLR−/− mice. After 6 weeks of feeding on an atherogenic diet, PI3Kd−/− recipient LDLR−/− mice displayed significantly impaired CD4+ and CD8+ T-cell numbers, CD4+ T-cell activation, CD4+ effector T cells, and proatherogenic CD4+ T helper (Th) 1 responses in para-aortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the net effect of PI3Kd deficiency was a substantial increase of aortic inflammation and atherosclerosis in LDLR−/− mice. Moreover, haematopoietic PI3Kd deficiency augmented macrophage accumulation in atherosclerotic plaques of LDLR−/− mice, whereas major macrophage functions including foam cell formation, efferocytosis, and cytokine secretion were unaffected by PI3Kd inactivation in these phagocytes. However, haematopoietic PI3Kd deficiency led to depletion of atheroprotective B-1 cells and reduction of proatherogenic B-2 cells in LDLR−/− mice. Moreover, haematopoietic PI3Kd deficiency caused a significant reduction of regulatory CD4+ T cells (Tregs) in plaques, para-aortic lymph nodes, and spleen of LDLR−/− mice. Furthermore, PI3Kd−/− Tregs exhibited reduced secretion of anti-inflammatory cytokines IL-10 and TGF-b as well as impaired suppression of CD4+ T-cell proliferation. Consequently, adoptive transfer of PI3Kd+/+ Tregs fully constrains the atherosclerotic burden in PI3Kd−/− transplanted LDLR−/− mice without affecting B cell numbers. Conclusions We demonstrate that PI3Kd plays a crucial role in B lymphocytes, Th1 cells, and Tregs during atherogenesis. Lack of PI3Kd signalling in atheroprotective Treg responses outplays its impact on proatherogenic Th1 responses, thus leading to aggravated atherosclerosis. Hence, PI3Kd is a key regulator of Treg biology and thereby protects against atherosclerosis progression. Acknowledgement/Funding Center for Molecular Medicine Cologne (CMMC) and the Marga and Walter Boll-Stiftung
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