RAS-p110α signalling in macrophages is required for effective inflammatory response and resolution of inflammation

Abstract

Abstract Macrophages play a critical role in the body's inflammatory response, and their functions are tightly regulated to ensure optimal immune system function. Here we show that RAS-p110α signalling, a pathway crucially involved in several biological processes and key for tumorigenesis, also exerts regulatory control over two critical aspects of the inflammatory response: monocyte extravasation during the initial stages of the inflammatory response and lysosomal function during the later stages. Disruption of this pathway in a genetically engineered mouse model, or through pharmacological intervention, leads to impaired inflammatory responses and delays resolution, consequently fostering the emergence of more severe and deleterious acute inflammatory reactions in vivo. Our findings shed light on a previously unknown role of the p110α isoform in the regulation of immune inflammatory responses in macrophages, providing a better understanding of the molecular mechanisms underlying the complex regulation of macrophage function in this process. Importantly, given recent evidence of the feasibility of activating p110α with small molecules, our results propose that the RAS-p110α pathway could serve as a promising pharmacological target for the treatment of chronic inflammation. This potential therapeutic avenue holds great promise for alleviating inflammatory disorders and fostering a better quality of life for patients suffering from such conditions.