Role of the Toll-like receptor pathway in the recognition of orthopedic implant wear-debris particles

Abstract

The inflammatory response to prosthetic implant-derived wear particles is the primary cause of bone loss and aseptic loosening of implants, but the mechanisms by which macrophages recognize and respond to particles remain unknown. Studies of innate immunity demonstrate that Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS). All TLRs signal through myeloid differentiation factor 88 (MyD88), except TLR3 which signals through TIR domain containing adapter inducing interferon-beta (TRIF), and TLR4 which signals through both MyD88 and TRIF. We hypothesized that wear-debris particles may act as PAMPs/DAMPs and activate macrophages via TLRs. To test this hypothesis, we first demonstrated that inhibition of MyD88 decreases polymethylmethacrylate (PMMA) particle-induced production of TNF-α in RAW 264.7 macrophages. Next we compared particle-induced production of TNF-α among MyD88 knockout (MyD88−/−), TRIF knockout (TRIF−/−), and wild type (WT) murine macrophages. Relative to WT, disruption of MyD88 signaling diminished, and disruption of TRIF amplified the particle-induced production of TNF-α. Gene expression data indicated that this latter increase in TNF-α was due to a compensatory increase in expression of MyD88 associated components of the TLR pathway. Finally, using an in vivo model, MyD88−/− mice developed less particle-induced osteolysis than WT mice. These results indicate that the response to PMMA particles is partly dependent on MyD88, presumably as part of TLR signaling; MyD88 may represent a therapeutic target for prevention of wear debris-induced periprosthetic osteolysis.

Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

“…Functional studies have shown that deletion of TLR2 and/or TLR4 in murine systems substantially reduces the in vitro and in vivo responses to titanium [8,37], UHMWPE [40], cobalt-chromium [85], and hydroxyapatite [34] particles. Moreover, similar results have also been obtained for deletion of the myeloid differentiation primary response gene (MyD88) with both PMMA and cobalt-chromium particles [82,85]. MyD88 is an adaptor protein involved in signaling by most TLRs and members of the IL-1 receptor family [51,79].…”

“…Moreover, there is extensive evidence that endogenous alarmins (also known as danger-associated molecular patterns) can activate TLRs [9,69]. A number of investigators have therefore concluded that TLR activation during aseptic loosening is primarily the result of alarmins rather than PAMPs [13,40,57,75,82]. For example, one of those papers concluded that UHMWPE particles induce production by monocytes of an alarmin known as hsp70 that, in turn, activates TLR4 [40].…”

Avoiding Immunosuppression for Islet Transplantation: Use of Protective Biomaterials

“…TLRs, upon recognition and binding of PAMPS to the receptor surface, initiate an intracellular signaling cascade ultimately resulting in the secretion of a host of inflammatory cytokines attributed to translocation of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) into the nucleus [65].…”

Immunological Challenges Facing Translation of Alginate Encapsulated Porcine Islet Xenotransplantation to Human Clinical Trials

“…These sensory receptors are one of many PRRs responsible for initiation of the innate immune response [ 7 ]. TLRs, upon recognition and binding of PAMPS to the receptor surface, initiate an intracellular signaling cascade ultimately resulting in the secretion of a host of infl ammatory cytokines attributed to translocation of the Nf-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) into the nucleus [ 8 ]. Capsule permeable antigens are secreted by islets, potentially as DAMPs due to hypoxic conditions generated by pericapsular fi brotic overgrowth.…”