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

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.

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 Creators:
Grimm, Myriam1, Author              
Tischner, Denise1, Author              
Troidl, Kerstin1, Author              
Albarran Juarez, Julian Alberto1, Author              
Sivaraj, Kishor K.1, Author              
Bouzas, Nerea Ferreiros, Author
Geisslinger, Gerd, Author
Binder, Christoph J., Author
Wettschureck, Nina1, Author              
Affiliations:
1Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591696              

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Free keywords: G-PROTEINS; CHOLESTEROL EFFLUX; NATURAL IGM; ATHEROSCLEROSIS; CELLS; RHO; INFLAMMATION; EXPRESSION; MIGRATION; RACHematology; Cardiovascular System & Cardiology; atherosclerosis; gene expression; GTP-binding proteins; macrophages; signal transduction;
 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.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Source Genre: Journal
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Publ. Info: TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA : LIPPINCOTT WILLIAMS & WILKINS
Pages: - Volume / Issue: 36 (1) Sequence Number: - Start / End Page: 37 - 48 Identifier: ISSN: 1079-5642