Angiotensin-(1-7) Promotes Resolution of Neutrophilic Inflammation in a Model of Antigen-Induced Arthritis in Mice

Abstract

Defective resolution of inflammation may be crucial for the initiation and development of chronic inflammatory diseases, such as arthritis. Therefore, it has been suggested that therapeutic strategies based on molecules that facilitate inflammation resolution present great potential for the treatment of chronic inflammatory diseases. In this study, we investigated the effects and role of angiotensin-(1-7) [Ang-(1-7)] in driving resolution of neutrophilic inflammation in a model of arthritis. For this purpose, male C57BL/6 mice were subjected to antigen-induced arthritis and treated with Ang-(1-7) at the peak of the inflammatory process. Analysis of the number of inflammatory cells, apoptosis, and immunofluorescence for NF-κB was performed in the exudate collected from the knee cavity. Neutrophil accumulation in periarticular tissue was measured by assaying myeloperoxidase activity. Apoptosis of human neutrophil after treatment with Ang-(1-7) was evaluated morphologically and by flow cytometry, and NF-κB phosphorylation by immunofluorescence. Efferocytosis was evaluated in vivo. Therapeutic treatment with Ang-(1-7) at the peak of inflammation promoted resolution, an effect associated with caspase-dependent neutrophils apoptosis and NF-κB inhibition. Importantly, Ang-(1-7) was also able to induce apoptosis of human neutrophils, an effect associated with NF-κB inhibition. The pro-resolving effects of Ang-(1-7) were inhibited by the Mas receptor antagonist A779. Finally, we showed that Ang-(1-7) increased the efferocytic ability of murine macrophages. Our results clearly demonstrate that Ang-(1-7) resolves neutrophilic inflammation in vivo acting in two key step of resolution: apoptosis of neutrophils and their removal by efferocytosis. Ang-(1-7) is a novel mediator of resolution of inflammation.

Effect of preventive or therapeutic treatment with angiotensin 1–7 in a model of bleomycin-induced lung fibrosis in mice

“…Here, we showed that the preventive treatment with Ang‐(1‐7) caused reduction in the number of neutrophils and mononuclear cells in the lungs of mice given BLM. The ability of Ang‐(1‐7) to prevent neutrophil influx could be due to a direct effect on neutrophil migration in vivo or the ability of this compound to induce neutrophil apoptosis and resolution . The exact mechanism by which Ang‐(1‐7) causes inhibition of neutrophil migration was not investigated here, but there was a clear reduction in neutrophil numbers and an increase in number of apoptotic cells in animals given preventive Ang‐(1‐7) treatment.…”

“…Ang‐(1‐7) has been shown to have anti‐inflammatory and proresolutive effects in murine models of arthritis and asthma . Due to this, we wondered if the oral treatment with Ang‐(1‐7) would decrease inflammation and collagen deposition in a model of pulmonary fibrosis induced by BLM.…”

“…Ang-(1-7) has been shown to have anti-inflammatory and proresolutive effects in murine models of arthritis and asthma. 16,17 Neutrophils are thought to play an important role in the activation of fibrogenesis. 23 Here, we showed that the preventive treatment with Ang-(1-7) caused reduction in the number of neutrophils and mononuclear cells in the lungs of mice given BLM.…”

“…The ability of Ang-(1-7) to prevent neutrophil influx could be due to a direct effect on neutrophil migration in vivo 24 or the ability of this compound to induce neutrophil apoptosis and resolution. 16 The exact mechanism by which Ang-(1-7)…”

“…Previous experiments have shown that Ang‐(1‐7) did not affect baseline parameters in the lung . The dose of Ang‐(1‐7) chosen was shown to cause significant decrease in various parameters in other models of inflammation . The weight of animals was evaluated on every 3 days and any death daily.…”