Phosphoinositide 3-kinase gamma (PI3Kgamma) has been depicted as a major regulator of inflammatory processes, including leukocyte activation and migration towards several chemokines. This study aims to explore the role of PI3Kgamma in the murine model of antigen-induced arthritis (AIA).
Development of AIA was investigated in wildtype and PI3Kgamma-deficient mice as well as in mice treated with a specific inhibitor of PI3Kgamma (AS-605240) in comparison to untreated animals. Inflammatory reactions of leukocytes, including macrophage and T cell activation, and macrophage migration, were studied in vivo and in vitro.
Genetic deletion or pharmacological inhibition of PI3Kgamma induced a marked decrease of clinical symptoms in early AIA, together with a considerably diminished macrophage migration and activation (lower production of NO, IL-1beta, IL-6). Also, macrophage and neutrophil infiltration into the knee joint were impaired in vivo. However, T cell functions, measured by cytokine production (TNFalpha, IFNgamma, IL-2, IL-4, IL-5, IL-17) in vitro and DTH reaction in vivo were not altered, and accordingly, disease developed normally at later timepoints
PI3Kgamma specifically affects phagocyte function in the AIA model but has no impact on T cell activation.