Wear particles promote endotoxin tolerance in macrophages by inducing interleukin‐1 receptor‐associated kinase‐M expression

Abstract

Toll-like receptors (TLRs) recognizing pathogen-associated molecular patterns (PAMP) play a role in local immunity and participate in implant-associated loosening. TLRs-mediated signaling is regulated by interleukin-1 receptor-associated kinase-M (IRAK-M). Our previous studies have proved that IRAK-M is induced by wear particles in macrophages from periprosthetic tissues. In this study, the IRAK-M-related mechanisms were further explored by lipopolysaccharide (LPS) and/or titanium (Ti) particles stimulations and small interfering RNAs (siRNAs). The protein level of IRAK-M was studied using western blotting and tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels were measured using ELISA. Results showed that in RAW264.7 cells stimulated by LPS after Ti particle pre-exposure, IRAK-M was slightly changed, compared with LPS stimulation. And levels of TNF-α and IL-1β in cultures stimulated by LPS first after Ti particle pre-exposure were lower than in the other two groups which were stimulated by LPS with or without Ti particles (p < 0.001), whereas there were no statistic differences between the later two (p > 0.05). The cytokines were lowest in Ti particles alone stimulation. After siRNAs silenced, IRAK-M-deficient cells exhibited increased expression of the cytokines in LPS stimulation after Ti particle pre-exposure and when stimulated with Ti particles alone. Our findings suggest that debris-induced IRAK-M decreases foreign body reactions, but at the same time, the over-expression of IRAK-M may also be detrimental on local intrusion of PAMPs or bacteria, negatively regulates the LPS-induced and TLRs-mediated inflammation and results in immunosuppression in periprosthetic tissue, which may predispose to implant-associated infections.

Potential proinflammatory and osteogenic effects of dicalcium silicate particles in vitro

“…Furthermore, LPS treatment of titanium particles increased TNF-α and IL-1β production in THP-1 cells [35] . In the present study, the C 2 S and HA samples were free of endotoxin contamination.…”

Recent advances in endotoxin tolerance

“…The primary cells induced by endotoxin tolerance usually are monocytes and macrophages . The key factor for endotoxin tolerance may be the sharp decrease of the expressions of TNF‐α and IL‐1β . However, the exact mechanism of endotoxin tolerance is still unclear up to date.…”

“…18 The key factor for endotoxin tolerance may be the sharp decrease of the expressions of TNF-α and IL-1β. 19 However, the exact mechanism of endotoxin tolerance is still unclear up to date. The key central immune organs (primary lymphoid organs) include the bone marrow and thymus, while peripheral immune organs (secondary lymphatic tissues) include spleen, tonsils, lymph vessels, lymph nodes, adenoids, liver, and skin.…”

Micrometer-Sized Titanium Particles Induce Aseptic Loosening in Rabbit Knee

“…The optimal animal model should accurately simulate the whole process of aseptic loosening induced by wear particles, although economic and practical factors must also be considered. Small animal models such as murine skull models are rapid, economical, and repeatable [ 11 ]; however, these models lack the implantation of simulated prostheses, which may better mimic the actual acute osteolysis process, and thus the mechanical fretting and local responses at the contact interface between the prosthesis and surrounding bone tissue cannot be simulated [ 12 ]. Although large animal models with real prosthesis implantation are ideal for the simulation of the mechanical loosening process of implanted prostheses, such models are difficult to implement on a large scale because of the high associated costs and decreased maneuverability associated with the highly technical operation required [ 13 – 15 ].…”