Abstract
It is widely recognized that innate macrophage immune reactions to implant debris are central to the inflammatory responses that drive biologic implant failure over the long term. Less common, adaptive lymphocyte immune reactions to implant debris, such as delayed type hypersensitivity (DTH), can also affect implant performance. It is unknown which key patient factors, if any, mediate these adaptive immune responses that potentiate particle/macrophage mediated osteolysis. The objective of this investigation was to determine to what degree known adaptive immune responses to metal implant debris can affect particle-induced osteolysis (PIO); and if this pathomechanism is dependent on: 1) innate immune danger signaling, i.e., NLRP3 inflammasome activity, 2) sex, and/or 3) age. We used an established murine calvaria model of PIO using male and female wild-type C57BL/6 vs. Caspase-1 deficient mice as well as young (12–16 weeks old) vs. aged (18–24 months old) female and male C57BL/6 mice. After induction of metal-DTH, and Cobalt-alloy particle (ASTM F-75, 0.4um median diameter) calvaria challenge, bone resorption was assessed using quantitative micro-computed tomography (micro-CT) analysis and immune responses were assessed by measuring paw inflammation, lymphocyte transformation test (LTT) reactivity and adaptive immune cytokines IFN-gamma and IL-17 (ELISA). Younger aged C57BL/6 female mice exhibited the highest rate and severity of metal sensitivity lymphocyte responses that also translated into higher PIO compared to any other experimental group. The absence of inflammasome/caspase-1 activity significantly suppressed DTH metal-reactivity and osteolysis in both male and female Caspase-1 deficient mice. These murine model results indicate that young female mice are more predisposed to metal-DTH augmented inflammatory responses to wear debris, which is highly influenced by active NLRP3 inflammasome/caspase-1 danger signaling. If these results are clinically meaningful for orthopedic patients, then younger female individuals should be appropriately assessed and followed for DTH derived peri-implant complications.
Highlights
The prevalence of total joint arthroplasties (TJAs) within the population is increasing as the number of TJAs performed yearly in the U.S is expected to rise to 4 million per year by 2030 [1]
Recent evidence has demonstrated that the incidence and severity of metal sensitization in TJA patients is increased compared to the general population, indicating an association with immune reactions to increased exposure to metals [64]
Male and female BL/6 metal-delayed-type hypersensitivity reaction (DTH) mice exhibited significantly increased paw inflammation vs respective controls (Fig 1B and 1C), i.e., Male BL/6 metal-DTH p = 0.01; female metal-DTH BL/6 mice p = 0.04). Both male and female Caspase-1 -/- metal-DTH mice had significantly less metal-DTH paw inflammation responses when compared to metal-DTH BL/6 mice. Both male and female wild-type mice were susceptible to developing paw inflammation DTH responses to implant metal degradation products, which was dependent on having functional NLRP3 inflammasome/Caspase-1 activity
Summary
The prevalence of total joint arthroplasties (TJAs) within the population is increasing as the number of TJAs performed yearly in the U.S is expected to rise to 4 million per year by 2030 [1]. NLRP3 inflammasome is a critical component of the innate immune system and can be activated by a diverse number of cellular irritants and endogenous damage signals such as ionic flux, reactive oxygen species (ROS), mitochondrial and lysosomal damage [14,15,16]. Exogenous danger signals such as silica, aluminum salt crystals and implant wear debris result in assembly and activation of the NLRP3 inflammasome [13, 17,18,19,20,21,22,23,24]. The inflammatory host response by macrophages of the innate immune system to implant wear particles are a leading pathomechanism driving inflammation and bone loss around implant-tissue interfaces
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