Anti-inflammatory effects of Ang-(1-7) via TLR4-mediated inhibition of the JNK/FoxO1 pathway in lipopolysaccharide-stimulated RAW264.7 cells.

Targeting inflammation is considered a challenging pharmacological strategy to prevent or delay the development of inflammatory diseases, such as severe asthma, Crohn's disease, and rheumatoid arthritis. The angiotensin-(1-7) -Mas axis ((Ang-(1-7)-Mas axis) was confirmed to antagonize the effects of the Angiotensin II-AT receptor axis and the latter is reported to regulate cardiovascular and renal function, as well as contribute to the inflammatory process. In this paper, we aim to explore the crucial effect of Ang-(1-7) in inflammation and disclose the mechanisms in lipopolysaccharide (LPS)-induced murine macrophages RAW264.7. We found that Ang-(1-7) inhibited the production and secretion of tumor necrosis factor-α and interleukin-6 in a concentration-dependent manner in LPS-induced macrophages. The overexpression of TLR4, phospho-JNK, and FoxO1 induced by LPS were also inhibited by incubation with Ang-(1-7). These inhibitory effects were reversed by A-779. Moreover, we also used a selective JNK inhibitor Sp600125 to further corroborate the involvement of TLR4, JNK, and FoxO1 in the anti-inflammatory action of Ang-(1-7). Our research reveals a new mechanism that Ang-(1-7) may drive anti-inflammatory effects via the Mas receptor through inhibition of the TLR4-mediated JNK/FoxO1 signaling pathway in LPS-induced macrophages. Our findings open new perspectives of Ang-(1-7)-Mas axis in local inflammation.