The metal nanoparticle-induced inflammatory response is regulated by SIRT1 through NF-κB deacetylation in aseptic loosening

Abstract

Aseptic loosening is the most common cause of total hip arthroplasty (THA) failure, and osteolysis induced by wear particles plays a major role in aseptic loosening. Various pathways in multiple cell types contribute to the pathogenesis of osteolysis, but the role of Sirtuin 1 (SIRT1), which can regulate inflammatory responses through its deacetylation, has never been investigated. We hypothesized that the downregulation of SIRT1 in macrophages induced by metal nanoparticles was one of the reasons for osteolysis in THA failure. In this study, the expression of SIRT1 was examined in macrophages stimulated with metal nanoparticles from materials used in prosthetics and in specimens from patients suffering from aseptic loosening. To address whether SIRT1 downregulation triggers these inflammatory responses, the effects of the SIRT1 activator resveratrol on the expression of inflammatory cytokines in metal nanoparticle-stimulated macrophages were tested. The results demonstrated that SIRT1 expression was significantly downregulated in metal nanoparticle-stimulated macrophages and clinical specimens of prosthesis loosening. Pharmacological activation of SIRT1 dramatically reduced the particle-induced expression of inflammatory cytokines in vitro and osteolysis in vivo. Furthermore, SIRT1 regulated particle-induced inflammatory responses through nuclear factor kappa B (NF-κB) acetylation. Thus, the results of this study suggest that SIRT1 plays a key role in metal nanoparticle-induced inflammatory responses and that targeting the SIRT1 pathway may lead to novel therapeutic approaches for the treatment of aseptic prosthesis loosening.

Reduction of Silent Information Regulator 1 Activates Interleukin-33/ST2 Signaling and Contributes to Neuropathic Pain Induced by Spared Nerve Injury in Rats

“…SIRT1 is an important deacetylase that directly deacetylates NF-κB (Deng et al, 2017). In addition, IL-33 can activate NF-κB through binding to ST2 (Numata et al, 2016).…”

Resveratrol decreases TNFα-induced ICAM-1 expression and release by Sirt-1-independent mechanism in intestinal myofibroblasts

“…These data confirm that, in our experimental conditions, RE does not involve Sirt-1 in the inhibition of NF-κB, considering also that 50 μM RE inhibits NF-κB and this is in agreement with ROS levels and ICAM-1 expression but not with Sirt-1 expression level. Indeed, in murine macrophages, RE also regulates the inflammatory responses by decreasing and increasing ac-NF-κB and IκB-α levels, respectively, without affecting total NF-κB levels [65]. However, these effects in macrophages are reversed by EX527 treatment [65] differently to that occurs in 18Co cells, in which EX527 reverses the effect of RE on NF-κB acetylation but not on IκB-α and ICAM-1 levels.…”

“…Indeed, in murine macrophages, RE also regulates the inflammatory responses by decreasing and increasing ac-NF-κB and IκB-α levels, respectively, without affecting total NF-κB levels [65]. However, these effects in macrophages are reversed by EX527 treatment [65] differently to that occurs in 18Co cells, in which EX527 reverses the effect of RE on NF-κB acetylation but not on IκB-α and ICAM-1 levels. 50 μM PDTC, with antioxidant properties often related to its inhibitory role on NF-κB [66,67], and NAC restore IκB-α values, but not ICAM-1 levels to control values in TNFα-stimulated 18Co.…”

Nanosized Alumina Particle and Proteasome Inhibitor Bortezomib Prevented inflammation and Osteolysis Induced by Titanium Particle via Autophagy and NF-κB Signaling

“…Considerable evidences suggest that Ti wear particles can induce the inflammatory reaction, while high dose of Ti particles exceeding the toxic level will lead to cells aoptosis and necrosis probably [21][22][23] . Macrophages, osteoblast, osteoclast, fibroblasts, mesenchymal stem cell (MSC), and T cells will secrete numerous proinflammatory chemokines and cytokines in response to wear particles stimulate, such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), prostaglandin E2, and macrophage colony stimulating factor (M-CSF) 5,[24][25][26][27][28][29][30] . Subsequently, the secretion of various cytokines will stimulate the expression of the receptor activator of NF-kB ligand (RANKL), an essential factor for regulating bone remodeling.…”

“…Bortezomib (BTZ), which is one of the reversible proteasome inhibitors, has been shown to be a potent inhibitor of NF-κB 38,39 . Bortezomib could block the nuclear transport of NF-kappaB, mainly by inhibiting the chymotryptic activity of polyubiquitinated protein degradation in 26S proteasome 30,[40][41][42][43] . Bortezomib at the first has been approved by FDA as a drug for the therapy of tumor, but it is now also considered as a remedy for non-tumorous diseases such as inflammation diseases [44][45][46] .…”