Effect of Aging on the Macrophage Response to Titanium Particles

Abstract

Macrophage-mediated inflammatory reaction to implant wear particles drives bone loss around total joint replacements (TJR). Although most TJR recipients are elderly, studies linking wear particle-activated macrophages and peri-implant osteolysis have not taken into account the multiple effects that aging has on the innate immune system and, in particular, on macrophages. To address this, we compared the wear particle responses of bone marrow macrophages obtained from young (2-month) and aged (18-month) mice. Macrophages were polarized to M0, M1, or M2 phenotypes in vitro, challenged with titanium particles, and their inflammatory response was characterized at multiple time points by quantitative reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. In addition, age-dependent changes in activation of transcription factor nuclear factor-κB were analyzed by a lentiviral vector-based luciferase reporter system. The particle stimulation experiment was further repeated using human primary macrophages isolated from blood donors of different ages. We found that the pro-inflammatory responses were generally higher in macrophages obtained from young mice, but differences between the age groups remained small and of uncertain biological significance. Noteworthily, M2 polarization effectively suppressed the particle-induced inflammation in both young and aged macrophages. These results suggest that aging of the innate immune system per se plays no significant role in the response of macrophages to titanium particles, whereas induction of M2 polarization appears a promising strategy to limit macrophage-mediated inflammation regardless of age.

Tumor necrosis factor primes and metal particles activate the NLRP3 inflammasome in human primary macrophages

“…These results are in line with two recent studies, in which sterile Ti particles induced neither NF-κB activation nor IL-1β secretion from murine macrophages [32,33]. At the same time, our results are different from previous reports, in which Ti and Cr-Mo alloy particles, without an additional priming signal, induced macrophage-mediated IL-1β secretion [10,12,15].…”

Metal-induced delayed type hypersensitivity responses potentiate particle induced osteolysis in a sex and age dependent manner

“…Thus, inflamm-aging is regarded as a delicate and intricate balance between pro- and anti- innate and adaptive inflammatory responses. Recently, it has been demonstrated that titanium-particle in vitro challenged macrophages from young 2-month-old male C57BL/6 mice expressed increased mRNA expression of cytokines IL-1β, IL-6 and TNF-α compared to aged macrophages from 18-month-old male C57BL/6 mice [ 72 ]. While in vitro metal-stimulated macrophages from aged mice produced increased amounts of IL-1 receptor antagonist (IL-1Ra), an anti-inflammatory cytokine that is central to suppressing IL-1β pro-inflammatory activity [ 72 ].…”

“…Recently, it has been demonstrated that titanium-particle in vitro challenged macrophages from young 2-month-old male C57BL/6 mice expressed increased mRNA expression of cytokines IL-1β, IL-6 and TNF-α compared to aged macrophages from 18-month-old male C57BL/6 mice [ 72 ]. While in vitro metal-stimulated macrophages from aged mice produced increased amounts of IL-1 receptor antagonist (IL-1Ra), an anti-inflammatory cytokine that is central to suppressing IL-1β pro-inflammatory activity [ 72 ]. It has also been reported aged healthy individuals (> 65 years) compared to young individuals (< 40 years), exhibited a decreased frequency of not only IL-17 producing CD4+ T cells but also a decrease ratio of IL-17 to IFN-gamma producing T cells (i.e.…”

Interleukin‐4 repairs wear particle induced osteolysis by modulating macrophage polarization and bone turnover

“…Modulation of macrophage polarization with IL‐4 has emerged as a means to prevent wear particle induced inflammation and osteolysis 10‐14 . In this study, the efficacy of IL‐4 treatment in repairing osteolytic lesions was assessed in a novel modification of a murine continuous femoral intramedullary particle infusion model.…”

“…Biomaterial wear particles activate macrophages into an inflammatory, M1‐like, phenotype characterized by continued production of pro‐inflammatory cytokines and chemokines with detrimental effects on the surrounding bone 2‐5 . In contrast, induction of M2 macrophage polarization by interleukin‐4 (IL‐4) treatment mitigates wear particle‐induced macrophage activation and inflammation in cell culture models 10‐12 . Corresponding results were obtained using a mouse calvarial model in which local IL‐4 injections significantly reduced acute UHMWPE particle‐induced inflammation and osteolysis 13 .…”