Innate immune reactions in septic and aseptic osteolysis around hip implants

Abstract

According to the long-standing definition, septic and aseptic total joint replacement loosening are two distinct conditions with little in common. Septic joint replacement loosening is driven by bacterial infection whereas aseptic loosening is caused by biomaterial wear debris released from the bearing surfaces. However, recently it has been recognized that the mechanisms that drive macrophage activation in septic and aseptic total joint replacement loosening resemble each other. In particular, accumulating evidence indicates that in addition to mediating bacterial recognition and the subsequent inflammatory reaction, toll-like receptors (TLRs) and their ligands, pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS), play a key role in wear debris-induced inflammation and macrophage activation. In addition, subclinical bacterial biofilms have been identified from some cases of seemingly aseptic implant loosening. Furthermore, metal ions released from some total joint replacements can activate TLR signaling similar to bacterial derived PAMPs. Likewise, metal ions can function as haptens activating the adaptive immune system similar to bacterial derived antigens. Thus, it appears that aseptic and septic joint replacement loosening share similar underlying pathomechanisms and that this strict dichotomy to sterile aseptic and bacterial-caused septic implant loosening is somewhat questionable. Indeed, rather than being two, well-defined clinical entities, peri-implant osteolysis is, in fact, a spectrum of conditions in which the specific clinical picture is determined by complex interactions of multiple local and systemic factors.

Figures

FIG. 1

Typical interface tissue histopathology in aseptic and septic loosening. (a) Interface tissue developing around aseptically loose TJRs is characterized with macrophage infiltrates and foreign body giant cells. (b) Occasional T lymphocytes (arrowheads), identified by CD3 immunostaining, are scattered among macrophages but neutrophils and other lymphocyte subpopulations are absent. In contrast, the septic interface is characterized by (c) NE+ neutrophil infiltrates, (d) diffuse CD3+ T lymphocyte infiltrates, (e) nodular CD20+ B lymphocyte infiltrates, and (f) occasional CD138+ plasma cells (arrowheads).

FIG. 2

The “particle disease” theory in brief. Macrophages are activated by wear particles to produce chemokines and inflammatory mediators. Chemokines recruit additional monocytes into interface tissue, and inflammatory cytokines lead to increased ostoclastogenesis and bone resorption, primarily by increasing receptor activator of Nf-κB ligand (RANKL) and decresing osteoprotegeing (OPG) production from local fibroblasts and osteoblast. The exact mechanisms by which wear particles are recognized by macrophages and thus cause macrophage activation is still incompletely understood.

FIG. 3

Toll-like receptors (TLRs) in wear debris-induced macrophage activation. Wear particles accumulate and concentrate both exo- and endogenous danger signal molecules on their surfaces. These DAMPs and PAMPs are recognized primarily by TLR2/1, TLR2/6, and TLR4, which induce macrophage activation and production of inflammatory cytokines and chemokines by activating NF-κB and IRF3. Additionally, oxidized alkane polymers and cobalt ions can directly induce TLR signaling and macrophage activation.

FIG. 4

Toll-like receptors (TLRs) in aseptic interface tissue. (a) Interface tissue macrophages and foreign body giant cells express a spectrum of TLRs including TLR1, TLR2, TLR4, and TLR6 as evaluated by immunohistochemical staining. (b) The relative expression of several TLRs including TLR1, TLR2, TLR4, and TLR6 is significantly increased in aseptic interface tissue compared to osteoarthritic synovial tissue as evaluated by qRT PCR. (*) p < 0.05; (**) p < 0.01; (***) p < 0.001 as evaluated using Mann-Whitney U test. Data from Ref. .

FIG. 5

Adaptive immune system in aseptic and septic loosening. (a) UHMWPE and PMMA wear particles accumulate PAMPs and DAMPs on their surfaces and are sufficient to activate macrophages via TLRs and other pattern recognition receptors (PRRs), leading to production of pro-inflammatory cytokines and chemokines ultimately leading to aseptic osteolysis. Due to the lack of presentable antigen, the adaptive immune system is not activated and lymphocyte subpopulations are rare in the peri-implant tissues. (b) In the case of metal wear, cobalt ions can activate macrophages directly via TLR activation and indirectly by inducing cell necrosis and release of large amounts of DAMPs. In addition, at least in genetically susceptible individuals, cobalt ions can activate adaptive immune system by forming haptens with host proteins. T helper type 1 lymphocytes enhance macrophages inflammatory responses by secreting interferon-γ that induce M1 polarization. As a marker of this lymphocyte activation, various lymphocyte subpopulations are characteristic for the adverse host reaction against metals. (c) In fulminant septic loosening, dividing bacteria provide both the danger signal and a plentitude of various antigens to activate the adaptive immune system.