IL-38 suppresses macrophage M1 polarization to ameliorate synovial inflammation in the TMJ via GLUT-1 inhibition

Abstract

ObjectivesInterleukin (IL)-38 was discovered as an anti-inflammatory factor. However, IL-38′s role in M1 macrophage polarization in the temporomandibular joint (TMJ) and the related mechanism are still unclear. We aimed to explore the effect and the mechanism of IL-38 on synovial inflammation in the TMJ in this study. MethodsThe expression of IL-38 in the TMJ synovium and macrophages was determined using immunohistochemistry (IHC) and Western blotting (WB). M1 macrophage polarization was induced by LPS, the macrophages were pre-treated with IL-38, and the levels of inflammatory markers associated with M1 macrophages were measured. To assess the mechanism of IL-38, small-interfering RNA (siRNA)‐GLUT-1 and STF31 were administered to macrophages, and the affected pathways were identified by WB. The effect of macrophage-conditioned medium (CM) on chondrocyte function was also determined. Finally, a mouse model of CFA‐induced TMJ inflammation was established. Histological staining and IHC were used to determine the effect of IL-38. ResultsIL-38 was detected at high levels in macrophages after lipopolysaccharide (LPS)challenge, and IL-38 downregulated M1 macrophage-related proinflammatory markers (iNOS, IL-6, TNF-α, and COX-2) in vitro. IL-38 suppressed M1 polarization by inhibiting GLUT-1 expression, NF-κB signaling, and MAPK signaling. Intriguingly, CM from macrophages that were pretreated with IL-38 and STF31 decreased inflammatory protein expression in chondrocytes. In addition, intra-articular injection of recombinant IL-38 ameliorated synovial inflammation in the TMJ by inhibiting M1 macrophage polarization and suppressing cartilage inflammation in vivo. ConclusionsIL-38 is a novel anti-inflammatory factor that contributes to alleviating TMJ inflammation by inhibiting macrophage M1 polarization, thereby ameliorating chondrocyte inflammation and restoring TMJ homeostasis.