Implant-derived titanium particles impair macrophage bacterial clearance via TRPC1 and lysosomal dysfunction.

Peri-implantitis (PI) is a treatment-resistant inflammatory condition that affects millions of patients with dental implants, leading to destructive loss of jawbone, implant failure, and escalating healthcare costs. It is classically attributed to bacterial biofilms; however, unlike periodontitis, it frequently progresses despite resolution of infection with standard antimicrobial therapy, suggesting a critical gap in our understanding of host-response dysfunction. Here, we identify implant-derived titanium particles (i-TiPs) as a persistent, abiotic pathogenic co-factor that impairs macrophage immune function by disrupting TRPC1-dependent Ca2+ signaling and lysosomal integrity. Mechanistically, we demonstrate that i-TiPs inhibit bacterial clearance by triggering dysregulated Ca2+ influx and lysosomal alkalinization, leading to defective phagolysosome maturation and increased inflammatory cytokine release. In vivo, TRPC1 knockout (trpc1-/-) mice challenged with i-TiPs maintain effective bacterial clearance, exhibit reduced cytokine responses, and develop significantly smaller titanium-mediated abscesses. These findings uncover a particle-induced host immune failure mechanism that explains PI's clinical resistance to antibiotics and underscore the need for adjunctive host modulation strategies beyond antimicrobial treatments to restore immune competence. In summary, this study demonstrates that i-TiPs fundamentally alter the host immune response to bacteria and act as a critical co-factor in the pathogenesis of PI. More broadly, our work positions the peri-implant microenvironment as a high-impact model system for investigating how abiotic exposomes, such as medical implant debris, alter host-microbe interactions and immune regulation in chronic disease.