Angiotensin-(1-7) and Alamandine Promote Anti-inflammatory Response in Macrophages In Vitro and In Vivo.

The renin-angiotensin system (RAS) peptides play an important role in inflammation. Resolution of inflammation contributes to restore tissue homeostasis, and it is characterized by neutrophil apoptosis and their subsequent removal by macrophages, which are remarkable plastic cells involved in the pathophysiology of diverse inflammatory diseases. However, the effects of RAS peptides on different macrophage phenotypes are still emerging. Here, we evaluated the effects of angiotensin-(1-7) (Ang-(1-7)) and the most novel RAS peptide, alamandine, on resting (M0), proinflammatory M(LPS+IFN-γ), and anti-inflammatory M(IL-4) macrophage phenotypes in vitro, as well as on specific immune cell populations and macrophage subsets into the pleural cavity of LPS-induced pleurisy in mice. Our results showed that Ang-(1-7) and alamandine, through Mas and MrgD receptors, respectively, do not affect M0 macrophages but reduce the proinflammatory TNF-α, CCL2, and IL-1ß transcript expression levels in LPS+IFN-γ-stimulated macrophages. Therapeutic administration of these peptides in LPS-induced inflammation in mice decreased the number of neutrophils and M1 (F4/80lowGr1+CD11bmed) macrophage frequency without affecting the other investigated macrophage subsets. Our data suggested that both Ang-(1-7) and alamandine, through their respective receptors Mas and MrgD, promote an anti-inflammatory reprogramming of M(LPS+IFN-γ)/M1 macrophages under inflammatory circumstances and potentiate the reprogramming induced by IL-4. In conclusion, our work sheds light on the emerging proresolving properties of Ang-(1-7) and alamandine, opening new avenues for the treatment of inflammatory diseases.

Angiotensin-(1-7) and Alamandine on Experimental Models of Hypertension and Atherosclerosis.

PURPOSE OF REVIEW: The purpose of this review was to summarize the current knowledge on the role of angiotensin-(1-7) [Ang-(1-7)] and alamandine in experimental hypertension and atherosclerosis. RECENT FINDINGS: The renin-angiotensin system (RAS) is a very complex system, composed of a cascade of enzymes, peptides, and receptors, known to be involved in the pathogenesis of hypertension and atherosclerosis. Ang-(1-7), identified and characterized in 1987, and alamandine, discovered 16 years after, are the newest two main effector molecules from the RAS, protecting the vascular system against hypertension and atherosclerosis. While the beneficial effects of Ang-(1-7) have been widely studied in several experimental models of hypertension, much less studies were performed in experimental models of atherosclerosis. Alamandine has shown similar vascular effects to Ang-(1-7), namely, endothelial-dependent vasorelaxation mediated by nitric oxide and hypotensive effects in experimental hypertension. There are few studies on the effects of alamandine on atherosclerosis.

Lack of interferon-gamma attenuates foreign body reaction to subcutaneous implants in mice.

Subcutaneous implantation of synthetic materials and biomedical devices often induces abnormal tissue healing - the foreign body reaction-which impairs their function. In particular, Interferon-γ (IFN-γ) is a critical endogenous mediator of inflammation and plays a key role in a wide variety of biological responses including tissue healing. However, the contribution of endogenous IFN-γ on different features of the foreign body response induced by synthetic implants regarding neovascularization, inflammation, and fibrogenesis is not well known. Here, we evaluated inflammatory angiogenesis and fibrogenesis induced by implantation of polyether-polyurethane sponges in mice targeted disrupted of the interferon-γ gene (IFN-γ-/- ) and wild-type (WT). The hemoglobin content, the number of vessels, and blood flow (evaluated by LDPI-laser Doppler perfusion imaging) were decreased in the implants from IFN-γ-/- as compared to WT mice. Likewise, neutrophils and macrophages accumulation (MPO and NAG activities, respectively) was decreased in IFN-γ-/- implants. Interestingly, while the local content of VEGF, TNF-α, CXCL-1/KC, as measured by ELISA, and iNOS expression, as measured by qPCR, were significantly reduced, the content of IL-10 was greatly increased in the implants from IFN-γ-/- mice as compared to WT mice. No alterations were observed in CCL-2/MCP-1 levels. Lastly, the collagen deposition, assessed by Picro-Sirius red-stained histological sections, was also reduced in IFN-γ-/- implants. Altogether, these data suggest that IFN-γ activity contributes to inflammatory angiogenesis and fibrogenesis in synthetic implants and that lack of IFN-γ expression attenuates foreign body reaction to implants in mice. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2243-2250, 2018.