TIPE2 modulates macrophage polarization via targeting Rac1/NF-kB and PI3K/AKT pathways

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disorder that affects up to 12% of the general population. It is associated with significant morbidity and a considerable burden on the healthcare system. Tumor necrosis factor -induced protein 8-like 2 (TIPE2) is an immune-related protein potentially involving the pathogenesis of autoimmune diseases, and depletion of TIPE2 can cause inflammatory diseases. In this study, we aimed to investigate the roles and mechanisms of TIPE2 in inflammation and macrophage polarization. A model of macrophage polarization was set up in phorbol-12-myristate-13-acetate-differentiated THP-1 monocytes. Once differentiated, THP-1 cells were treated with interleukin (IL)-4 to obtain M2 polarized macrophages or with interferon (IFN)- and lipopolysaccharide (LPS) for classical macrophage activation (M1). Cell surface markers (CD11b and CD206) were analyzed by flow cytometry. Protein levels of TIPE2, M1/M2 macrophages-associated inflammatory factors, and pathway-related genes were measured by western blotting. ELISA was conducted to measure the level of iNOS. TIPE2 upregulation inhibited the M1 polarization of macrophages. TIPE2 downregulation inactivated the M2 polarization of macrophages. TIPE2 overexpression inactivated the Rac1/NF-kB pathway in LPS/IFN-g-induced M1 macrophages. TIPE2 downregulation inactivated the PI3K/AKT pathway in IL-4-induced M2 macrophages. TIPE2 mediates macrophage polarization caused by LPS/IFN-g and IL-4 via the Rac1/NF-kB and PI3K/AKT pathways.