ABSTRACT
Inflammatory response in macrophages on account of prostheses-derived wear particles is the leading cause of artificial joint failure. However, the mechanism by which wear particles initiate macrophage inflammation has not been fully elucidated. Previous research studies have identified TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING) as potential factors in inflammation and autoimmune diseases. Here, we found that both TBK1 and STING were increased in synovium from aseptic loosening (AL) patients and were activated in titanium particles (TiPs)-stimulated macrophages. Lentivirus-mediated knockdown of TBK or STING significantly inhibited the inflammatory effects of macrophages, while overexpression of TBK or STING exerted opposite results. In concrete, STING/TBK1 promoted the activation of NF-κB and IRF3 pathways and macrophage M1 polarization. For further validation, a mice cranial osteolysis model was constructed for in vivo assays, and we found that STING-overexpressed lentivirus injection exacerbated osteolysis and inflammation, which was counteracted by TBK1-knockdown injection. In conclusion, STING/TBK1 enhanced TiP-induced macrophage inflammation and osteolysis via orchestrating the activation of NF-κB and IRF3 pathways and M1 polarization, which suggested STING/TBK1 as potential therapeutic targets for preventing AL of prostheses.
Subject(s)
Osteolysis , Titanium , Animals , Mice , Titanium/adverse effects , Titanium/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Osteolysis/chemically induced , Osteolysis/metabolism , Macrophages/metabolism , Inflammation/genetics , Inflammation/metabolismABSTRACT
As total joint replacement is widely applied for severe arthropathy, peri-prosthetic aseptic loosening as one of the main causes of implant failure has drawn wide attention. Wear particles such as titanium particles (TiPs) derived from prosthesis can initiate macrophages inflammation and sequentially activate osteoclasts, which results in bone resorption and osteolysis for long-term. Therefore, inhibiting wear particles induced macrophages inflammation is considered as a promising therapy for AL. In this research, we found that the inhibition of p110δ, a member of class IA PI3Ks family, could significantly dampen the TiPs-induced secretion of TNFα and IL-6. By the transfection of siRNA targeting p110δ, we confirmed that p110δ was responsible for TNFα and IL-6 trafficking out of Golgi complex without affecting their expression in TiPs-treated macrophages. As the upstream transcription-repressor of p110δ, Krüppel-like factor 4 (KLF4), targeted by miR-92a, could also attenuate TiPs-induced inflammation by mediating NF-κB pathway and M1/M2 polarization. To further ascertain the roles of KLF4/p110δ, TiPs-induced mice cranial osteolysis model was established and vivo experiments validated that KLF4-knockdown could exacerbate TiPs-induced osteolysis, which was strikingly ameliorated by knockdown of p110δ. In summary, our study suggests the key role of miR-92a/KLF4/p110δ signal in TiPs-induced macrophages inflammation and osteolysis.
