期刊名称:Proceedings of the National Academy of Sciences
印刷版ISSN:0027-8424
电子版ISSN:1091-6490
出版年度:2016
卷号:113
期号:49
页码:14109-14114
DOI:10.1073/pnas.1612668113
语种:English
出版社:The National Academy of Sciences of the United States of America
摘要:SignificanceThe alternative renin-angiotensin system pathway, the angiotensin (Ang)-(1-7)/Mas axis, may counterbalance Ang II-mediated proinflammatory effects. To investigate the role of the Ang-(1-7)/Mas axis in immune cell function and inflammatory diseases in vivo, we used two different chronic inflammatory animal models. Deletion of Mas affects macrophage function and phenotype independently of the underlying phagocyte stimulus and aggravates the clinical course of experimental autoimmune encephalomyelitis as well as atherosclerosis in mice by tipping the in vivo balance from M(IL-4+IL-13)- to M(LPS+IFN{gamma})-like macrophages. Thus, modulation of the Ang-(1-7)/Mas axis counteracts the proinflammatory role of Ang II by regulating the delicate equilibrium between M(LPS+IFN{gamma})- and M(IL-4+IL-13)-like macrophages, thereby representing a promising pharmacological target for chronic inflammatory diseases. Recently, an alternative renin-angiotensin system pathway has been described, which involves binding of angiotensin-(1-7) to its receptor Mas. The Mas axis may counterbalance angiotensin-II-mediated proinflammatory effects, likely by affecting macrophage function. Here we investigate the role of Mas in murine models of autoimmune neuroinflammation and atherosclerosis, which both involve macrophage-driven pathomechanisms. Mas signaling affected macrophage polarization, migration, and macrophage-mediated T-cell activation. Mas deficiency exacerbated the course of experimental autoimmune encephalomyelitis and increased macrophage infiltration as well as proinflammatory gene expression in the spleen and spinal cord. Furthermore, Mas deficiency promoted atherosclerosis by affecting macrophage infiltration and migration and led to increased oxidative stress as well as impaired endothelial function in ApoE-deficient mice. In summary, we identified the Mas axis as an important factor in macrophage function during inflammation of the central nervous and vascular system in vivo. Modulating the Mas axis may constitute an interesting therapeutic target in multiple sclerosis and/or atherosclerosis.
关键词:atherosclerosis ; EAE ; inflammation ; macrophages ; renin–angiotensin system