PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ in the joint microenvironment

Abstract

Background The cytoskeletal protein, PSTPIP2, is associated with inflammation and is predominantly expressed in macrophages. Previous data have shown that PSTPIP2 inhibits articular bone damage in arthritic rats. The aim of this study is to explore the molecular mechanism of PSTPIP2’s resistance to bone erosion. Methods In the current study, peripheral blood and surgically excised synovial tissue from RA patients, DBA/1 mice, Pstpip2CreR26-ZsGreen reporter mice, and Esr2fl/fl/Adgre-Cre tool mice were used for in vivo studies. Adeno-associated viral vector was used to overexpress PSPTIP2 protein in vivo. Results We found that The level of PSTPIP2 in synovial macrophages is negatively correlated with RA disease activity, which is mediated by synovial macrophages polarization. PSTPIP2hi synovial macrophages form a tight immunological barrier in the lining layer. Notably, the ability of PSTPIP2 to regulate synovial macrophages polarization is dependent on ERβ. Additionally, PSTPIP2 regulates the dynamics of synovial macrophages via ERβ. Conclusions Together, this study reveals that PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ to form an immunological barrier (F4/80+PSTPIP2hi cell-enriched zone) for the joints. Thus, local modulation of PSTPIP2 expression in the joint microenvironment may be a potential strategy for controlling bone erosion in rheumatoid arthritis. Graphical Abstract PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ to form F4/80+PSTPIP2hi cellular barrier in joint microenvironment.

The Impact of Microbiota–Immunity–Hormone Interactions on Autoimmune Diseases and Infection

“…Cytokines produced by the fetoplacental unit can modulate maternal immune responses, promoting a strong Th2 and decreasing Th1/Th17-mediated response to reduce the risks of miscarriage [ 172 , 173 ]. Estrogen/estrogen receptor (E2/ER) signaling plays an active role in the development, differentiation, and functionality of both innate and adaptive immune cells [ 174 , 175 , 176 ]. Indeed, a direct E2 role in regulating the function and differentiation of immune cells has been confirmed both in the healthy immune system and in several diseases [ 177 ].…”