Endosomal damage and TLR2 mediated inflammasome activation by alkane particles in the generation of aseptic osteolysis

Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Molecular Immunology (Impact Factor: 2.97). 10/2009; 47(2-3):175-84. DOI: 10.1016/j.molimm.2009.09.023
Source: PubMed

ABSTRACT Ultra-high molecular weight polyethylene is widely used as a bearing surface in prosthetic arthroplasty. Over time the generation of implant-derived wear particles can initiate an inflammatory reaction characterized by periprosthetic inflammation and ultimately bone resorption at the prosthetic bone interface. Herein we present evidence that the different sized particles as well as the different length alkane polymers generated by implant wear leads to a two component inflammatory response. Polymeric alkane structures, with side chain oxidations, directly bind and activate the TLR-1/2 signaling pathway. Whereas micron- and nanometer-sized particulate debris are extensively phagocyted and induce enlargement, fusion and disruption of endosomal compartments. The resulting lysosomal damage and subsequent enzymatic leakage induces the NALP3 inflammasome activation as determined by cathepsins S and B cytosolic release, Caspase 1 activation and processing of pro-IL-1beta, and pro-IL-18. These two processes synergistically results in the initiation of a strong inflammatory response with consequent cellular necrosis and extracellular matrix degradation.

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Available from: Laura Santambrogio, Sep 26, 2015
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    • "Past investigations have shown the importance of PAMPs (e.g., toll-like receptors, TLRs) in vivo, in the periprosthetic tissues of patients with aseptic loosening [45–47] and in TLR-knockout mouse models (MyD88 knockout mice) where lower amounts of cytokines and osteolysis were induced by polymethylmethacrylate (PMMA) implant debris particles than wild-type mice [20, 48]. The MyD88 dependent pathways of TLR signalling result in activation of nuclear factor NF-κB, which has been long shown to play a role in particle induced osteolysis and the production of proinflammatory cytokines such as TNFα, IL-1β, and IL-12, Figure 3  [49]. "
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    ABSTRACT: All of the over 1 million total joint replacements implanted in the US each year are expected to eventually fail after 15-25 years of use, due to slow progressive subtle inflammation at the bone implant interface. This inflammatory disease state is caused by implant debris acting, primarily, on innate immune cells, that is, macrophages. This slow progressive pathological bone loss or "aseptic loosening" is a potentially life-threatening condition due to the serious complications in older people (>75 yrs) of total joint replacement revision surgery. In some people implant debris (particles and ions from metals) can influence the adaptive immune system as well, giving rise to the concept of metal sensitivity. However, a consensus of studies agrees that the dominant form of this response is due to innate reactivity by macrophages to implant debris where both danger (DAMP) and pathogen (PAMP) signalling elicit cytokine-based inflammatory responses. This paper discusses implant debris induced release of the cytokines and chemokines due to activation of the innate (and the adaptive) immune system and the subsequent formation of osteolysis. Different mechanisms of implant-debris reactivity related to the innate immune system are detailed, for example, danger signalling (e.g., IL-1β, IL-18, IL-33, etc.), toll-like receptor activation (e.g., IL-6, TNF-α, etc.), apoptosis (e.g., caspases 3-9), bone catabolism (e.g., TRAP5b), and hypoxia responses (Hif1-α). Cytokine-based clinical and basic science studies are in progress to provide diagnosis and therapeutic intervention strategies.
    Mediators of Inflammation 05/2014; 2014:185150. DOI:10.1155/2014/185150 · 3.24 Impact Factor
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    • "224227). Particles of these two different size ranges were chosen according to their potential of different inflammasome complex activation (e.g., " frustrated phagocytosis " generated by large-sized particles or " endosomal destabilization " by readily phagocytized smaller particles) [24] [25]. After having been autoclaved, the particles were suspended in sterile cell culture medium for subsequent studies. "
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    ABSTRACT: Hypersensitivity reactions to titanium (Ti) are very rare. Thus, we assessed the proinflammatory response and also potential tolerance favoring in vitro reactivity of human blood lymphocytes and monocytes (PBMC) to Ti in healthy individuals (14 without, 6 with complication-free dental Ti implants). The proliferation index (SI) in lymphocyte transformation test (LTT) and production of cytokines linked to innate immune response (IL-1 β , IL-6, and TNF α ) or immune regulation (IL-10) were assessed in response to TiO2 particles or Ti discs. In both groups, the Ti-LTT reactivity was not enhanced (e.g., SI < 3). The control antigen tetanus toxoid (TT) gave adequate reactivity (median SI individuals without/with implant: 20.6 ± 5.97/19.58 ± 2.99). Individuals without implant showed higher cytokine response to Ti materials than individuals with symptom-free implants; for example, TiO2 rutile particle induced increase of IL-1 β 70.27-fold/8.49-fold versus control medium culture. PBMC of 5 of the 6 individuals with complication-free Ti implants showed an ex vivo ongoing production of IL-10 (mean 4.18 ± 2.98 pg/mL)-but none of the 14 controls showed such IL-10 production. Thus in vitro IL-1 β -, IL-6-, and TNF- α production reflects "normal" unspecific immune response to Ti. This might be reduced by production of tolerogenic IL-10 in individuals with symptom-free Ti dental implants.
    09/2013; 2013:539834. DOI:10.1155/2013/539834
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    • "These findings strongly supported that particles can be recognized through TLR, partly dependent on MyD88 signaling pathway. Maitra et al. reported that UHMWPE particles activated TLR1/TLR2, leading to an inflammatory program mediated by NF-κB-signaling pathway [50]. It has been reported that the p38 and JNK signaling pathways can mediate wear particle-induced osteoclast differentiation in vitro. "
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    ABSTRACT: Wear particle-induced periprosthetic osteolysis remains the principal cause of aseptic loosening of orthopaedic implants. Monocytes/macrophages phagocytose wear particles and release cytokines that induce inflammatory response. This response promotes osteoclast differentiation and osteolysis. The precise mechanisms by which wear particles are recognized and induce the accumulation of inflammatory cells in the periprosthetic tissue have not been fully elucidated. Recent studies have shown that toll-like receptors (TLRs) contribute to the cellular interaction with wear particles. Wear particles are recognized by monocytes/macrophages through TLRs coupled with the adaptor protein MyD88. After the initial interaction, wear particles induce both local and systemic migration of monocytes/macrophages to the periprosthetic region. The cellular migration is mediated through chemokines including interleukin-8, macrophage chemotactic protein-1, and macrophage inhibitory protein-1 in the periprosthetic tissues. Interfering with chemokine-receptor axis can inhibit cellular migration and inflammatory response. This paper highlights recent advances in TLR, and chemokine participated in the pathogenesis of aseptic loosening. A comprehensive understanding of the recognition and migration mechanism is critical to the development of measures that prevent wear particle-induced aseptic loosening of orthopaedic implants.
    BioMed Research International 10/2012; 2012:596870. DOI:10.1155/2012/596870 · 2.71 Impact Factor
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