Focal adhesion kinase acts on the PI3K/Akt/mTOR pathway to modulate wear particle-induced autophagy in macrophages.

Periprosthetic joint infection (PJI) is a devastating complication of total hip arthroplasty (THA) and is closely associated with innate immunity impairment. Typically, wear particles shed from prostheses can induce abnormal autophagy of macrophages that damages the innate immunity in periprosthetic tissues; however, the underlying mechanisms remain unclear. Herein, we report the role of focal adhesion kinase (FAK) in titanium (Ti) particle-induced autophagy. In vitro experiments revealed that FAK activation inhibited early-stage Ti-induced autophagy via the PI3K/Akt/mTOR pathway, whereas treatment with the FAK inhibitor PF573228 recovered autophagy to a certain degree. Our mouse calvarial model also revealed that PF573228 could prevent FAK-mediated downregulation of autophagy in macrophages at the early stage and can suppress inflammation and inflammatory osteolysis. In conclusion, FAK acts on the PI3K/Akt/mTOR pathway to modulate Ti-induced autophagy in macrophages. The use of inhibitors such as PF573228 could promote autophagy in macrophages to an appropriate level after prosthesis implantation, thereby preventing infection-related damage to periprosthetic tissues. Accordingly, FAK inhibitors can be developed as a novel therapeutic option for PJI.