Hematopoietic PI3Kδ deficiency aggravates murine atherosclerosis through impairment of Tregs
Mario Zierden, Eva Maria Berghausen, Leoni Gnatzy-Feik, Christopher Millarg, Felix Simon Ruben Picard, Martha Kiljan, Simon Geißen, Apostolos Polykratis, Lea Zimmermann, Richard Julius Nies, Manolis Pasparakis, Stephan Baldus, Chanil Valasarajan, Soni Savai Pullamsetti, Holger Winkels, Marius Vantler, Stephan Rosenkranz
Mario Zierden, Eva Maria Berghausen, Leoni Gnatzy-Feik, Christopher Millarg, Felix Simon Ruben Picard, Martha Kiljan, Simon Geißen, Apostolos Polykratis, Lea Zimmermann, Richard Julius Nies, Manolis Pasparakis, Stephan Baldus, Chanil Valasarajan, Soni Savai Pullamsetti, Holger Winkels, Marius Vantler, Stephan Rosenkranz
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Research Article Cardiology Immunology

Hematopoietic PI3Kδ deficiency aggravates murine atherosclerosis through impairment of Tregs

Abstract

Chronic activation of the adaptive immune system is a hallmark of atherosclerosis. As PI3Kδ is a key regulator of T and B cell differentiation and function, we hypothesized that alleviation of adaptive immunity by PI3Kδ inactivation may represent an attractive strategy counteracting atherogenesis. As expected, lack of hematopoietic PI3Kδ in atherosclerosis-prone Ldlr–/– mice resulted in lowered T and B cell numbers, CD4+ effector T cells, Th1 response, and immunoglobulin levels. However, despite markedly impaired peripheral pro-inflammatory Th1 cells and atheromatous CD4+ T cells, the unexpected net effect of hematopoietic PI3Kδ deficiency was aggravated vascular inflammation and atherosclerosis. Further analyses revealed that PI3Kδ deficiency impaired numbers, immunosuppressive functions, and stability of regulatory CD4+ T cells (Tregs), whereas macrophage biology remained largely unaffected. Adoptive transfer of wild-type Tregs fully restrained the atherosclerotic plaque burden in Ldlr–/– mice lacking hematopoietic PI3Kδ, whereas PI3Kδ-deficient Tregs failed to mitigate disease. Numbers of atheroprotective B-1 and pro-atherogenic B-2 cells as well as serum immunoglobulin levels remained unaffected by adoptively transferred wild-type Tregs. In conclusion, we demonstrate that hematopoietic PI3Kδ ablation promotes atherosclerosis. Mechanistically, we identified PI3Kδ signaling as a powerful driver of atheroprotective Treg responses, which outweigh PI3Kδ-driven pro-atherogenic effects of adaptive immune cells like Th1 cells.

Authors

Mario Zierden, Eva Maria Berghausen, Leoni Gnatzy-Feik, Christopher Millarg, Felix Simon Ruben Picard, Martha Kiljan, Simon Geißen, Apostolos Polykratis, Lea Zimmermann, Richard Julius Nies, Manolis Pasparakis, Stephan Baldus, Chanil Valasarajan, Soni Savai Pullamsetti, Holger Winkels, Marius Vantler, Stephan Rosenkranz

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Figure 3

Hematopoietic PI3Kδ deficiency aggravates atherosclerosis in Ldlr–/– mice.

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Hematopoietic PI3Kδ deficiency aggravates atherosclerosis in Ldlr–/– mic...
(A) Representative Oil Red O–stained aortic sinus sections and (B and C) quantification of atherosclerotic lesion size in the aortic sinus of PI3Kδ+/+→Ldlr–/– (blue) and PI3Kδ–/–→Ldlr–/– male mice (red) (n = 19–22; see Supplemental Figure 4A for quantification of atherosclerotic lesions at each of 4 levels analyzed per mouse). (D) Representative Sudan IV–stained en face preparation of whole aortas and (E and F) quantification of atherosclerotic burden in the whole aorta of male mice (n = 12–15). Atherosclerotic lesion areas are depicted as plaque area (μm2) and relative plaque area (lesion area as percentage of total vessel area), respectively. Representative aortic sinus sections immunohistochemically stained for (G) MOMA-2+ macrophages (red) and (I) CD4+ T cells (red) as well as (H) quantification of the macrophage content (n = 10–11) and (J) CD4+ T cell content (n = 10–13) in atherosclerotic lesions of indicated male mice. Statistics were done using 2-tailed unpaired t test. *P < 0.05, ***P < 0.001.