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S1P(2)/G(12/13) Signaling Negatively Regulates Macrophage Activation and Indirectly Shapes the Atheroprotective B1-Cell Population

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Grimm,  Myriam
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Tischner,  Denise
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Troidl,  Kerstin
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Albarran Juarez,  Julian Alberto
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Sivaraj,  Kishor K.
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Wettschureck,  Nina
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Grimm, M., Tischner, D., Troidl, K., Albarran Juarez, J. A., Sivaraj, K. K., Bouzas, N. F., et al. (2016). S1P(2)/G(12/13) Signaling Negatively Regulates Macrophage Activation and Indirectly Shapes the Atheroprotective B1-Cell Population. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 36(1), 37-48. doi:10.1161/ATVBAHA.115.306066.


Cite as: https://hdl.handle.net/21.11116/0000-0001-BEF4-6
Abstract
Objectives Monocyte/macrophage recruitment and activation at vascular predilection sites plays a central role in the pathogenesis of atherosclerosis. Heterotrimeric G proteins of the G(12/13) family have been implicated in the control of migration and inflammatory gene expression, but their function in myeloid cells, especially during atherogenesis, is unknown. Approach and Results Mice with myeloid-specific deficiency for G(12/13) show reduced atherosclerosis with a clear shift to anti-inflammatory gene expression in aortal macrophages. These changes are because of neither altered monocyte/macrophage migration nor reduced activation of inflammatory gene expression; on the contrary, G(12/13)-deficient macrophages show an increased nuclear factor-B-dependent gene expression in the resting state. Chronically increased inflammatory gene expression in resident peritoneal macrophages results in myeloid-specific G(12/13)-deficient mice in an altered peritoneal micromilieu with secondary expansion of peritoneal B1 cells. Titers of B1-derived atheroprotective antibodies are increased, and adoptive transfer of peritoneal cells from mutant mice conveys atheroprotection to wild-type mice. With respect to the mechanism of G(12/13)-mediated transcriptional control, we identify an autocrine feedback loop that suppresses nuclear factor-B-dependent gene expression through a signaling cascade involving sphingosine 1-phosphate receptor subtype 2, G(12/13), and RhoA. Conclusions Together, these data show that selective inhibition of G(12/13) signaling in macrophages can augment atheroprotective B-cell populations and ameliorate atherosclerosis.