Imunomodulação da resposta imune na artrite gotosa aguda murina através da reprogramação de macrófagos

Abstract

Gouty arthritis is an inflammation of the joints characterized by the deposition of MSU crystals (monosodium urate) within the joints. Within the context of gouty inflammation, macrophages play a paradoxical role, participating in both the pathogenesis and resolution of inflammation. These cells have the ability to adapt their activation profiles based on the tissue microenvironment and contribute to physiological and pathological processes in seeking to achieve homeostasis. The aim of this study was to investigate and evaluate the therapeutic potential of regulatory macrophages (Mreg), aiming to enhance the understanding and application of their effects in a gout model, focusing on reducing inflammatory symptoms and preventing joint damage. Consequently, in vitro studies were conducted using bone marrowderived macrophages (BMDMs) and in vivo experiments using gout models in mice. Reprogramming macrophages toward a regulatory profile led to a decrease in the release of IL-12 and an increase in the release of IL-10 compared to other macrophage subtypes. In in vitro studies, co-incubation of Mreg with LPS-primed macrophages and subsequent challenge with NLRP3 inflammasome agonists resulted in a reduction in the release of IL-1β, a key cytokine in gouty inflammation. Additionally, a decrease in IL-1β was observed in the model of acute peritonitis induced by MSU in mice upon injecting Mreg. Subsequently, MSU crystals were injected into the tibiofemoral joints of mice, resulting in tissue inflammation associated with a significant influx of leukocytes, mainly neutrophils. Administering Mreg therapy to the joints led to a reduction in the influx of neutrophils and the release of the chemokine CXCL1. These preliminary results provide perspectives for further investigations into the role of Mregs and IL-10 in the NLRP3 inflammasome pathway and inflammation reduction, as well as the potential for manipulating the macrophage phenotype. The study highlights macrophages as potential therapeutic targets in gout. Reprogramming macrophages towards an anti-inflammatory profile could be an effective approach in disease management. These findings have the potential to contribute to the development of innovative therapeutic strategies for gouty arthritis.