Increased Expression of Toll-like Receptors in Aseptic Loose Periprosthetic Tissues and Septic Synovial Membranes Around Total Hip Implants

Objective. Toll-like receptors (TLR) are transmembrane proteins found in various cells. They recognize infectious and endogenous threats, so-called danger signals, that evoke inflammation and assist adaptive immune reactions. It has been suggested that TLR play a role in periprosthetic tissues and arthritic synovium. Our objective was to elucidate tissue localization and functional roles of TLR in periprosthetic tissues in 2 different pathologic conditions, aseptic and septic implant loosening. Methods. For immunohistochemistry studies, aseptic synovial-like membranes of periprosthetic connective tissues (n = 15) and septic synovial capsular tissues (n = 5) were obtained at revision surgery and from salvage of infected totally replaced hips, respectively. Osteoarthritic synovial tissues were used for comparison (n = 5). Samples were processed for immunohistopathologic analyses for tissue colocalization of TLR with CD68 and/or CD 15 using the Alexa fluorescent system. Total RNA was isolated from frozen tissues and converted into cDNA, TLR 21 47 5 and 9 sequences were amplified, and the products were quantified using real-time polymerase chain reaction. Results. Immunofluorescent staining showed colocalization of TLR 2, 4, 5, and 9 with CD68 in the focal monocyte/macrophage aggregates in aseptic synovial-like membranes from loose total hip replacements. TLR 2, 4, 5, and 9 were also found colocalized with CD15+ poly morphonuclear leukocytes and CD68+ mononuclear cells of the synovial membranes from septic total hip replacements. In osteoarthritic synovial tissues, expression of TLR was found only in vascular cells and mononuclear cells, and the reactivity was weak. mRNA levels of TLR 27 4, 5, and 9 were increased in both aseptic and septic periprosthetic tissues. TLR 2 and 5 were significantly higher than TLR 4 and 9 in aseptic and septic samples. Conclusion. Peri-implant tissues were well equipped with TLR in both aseptic and septic conditions. TLR 2- and TLR 5-mediated responses seemed to dominate. In aseptic loosening, monocytes/macrophages were the main TLR-equipped cells apparently responsible for alarmin-induced responses. This could lead to production of inflammatory cytokines and extracellular matrix-degrading proteinases after phagocytosis of wear debris derived from an implant, but in septic cases they eventually respond to microbial components. Thus, inflammatory cells in both aseptic and septic tissues were equipped with TLR, providing them with responsiveness to both endogenous and exogenous TLR ligands. (First Release Feb 1 2009: J Rheumatol 2009;36:598-608; doi:10.3899/jrheum.080390)