Ipriflavone suppresses NLRP3 inflammasome activation in host response to biomaterials and promotes early bone healing

Abstract

Aim: Emerging studies have shown that immune response to biomaterial implants plays a central role in bone healing. Ipriflavone is clinically used for osteoporosis.However, the mechanism of ipriflavone in immune response to implants in early stages of osseointegration remains unclear. In this study, we aimed to investigate the potential role of ipriflavone in early bone healing process and uncover the underlying mechanism. Materials and Methods:We carried out histological examination as well as analysis of proinflammatory cytokines and NLRP3 inflammasome activation in a tibial implantation mouse model with intra-peritoneal injection of ipriflavone. In addition, we explored the mechanism of ipriflavone in the regulation of NLRP3 inflammasome activation in macrophages.Results: In vivo, ipriflavone ameliorated host inflammatory response related to NLRP3 inflammasome activation at implantation sites, characterized by reductions of inflammatory cell infiltration and proinflammatory cytokine interleukin-1β levels.Ipriflavone treatment also showed beneficial effects on early osseointegration. Further investigations of the molecular mechanism showed that the suppression of NLRP3 inflammasome acts upstream of NLRP3 oligomerization through abrogating the production of reactive oxygen species.Conclusions: These results revealed an anti-inflammatory role of ipriflavone in NLRP3 inflammasome activation through improving mitochondrial function. This study provides a new strategy for the development of immune-regulated biomaterials and treatment options for NLRP3-related diseases.

The inflammasome in biomaterial‐driven immunomodulation

“…Chen et al. ( 2022 ) investigated the early inflammatory response to titanium screws in bone, and concluded that the administration of ipriflavone, a natural isoflavone, decreased the activation of the NLRP3 inflammasome in macrophages. They reported the interesting osteoimmunomodulatory effect of ipriflavone that targets the NLRP3 inflammasome, thus having an anti‐inflammatory effect.…”

“…They further concluded that the administration of ATP, which is a ligand for NLRP3, leads to the activation of inflammasomes causing the up-regulation of the expression of pro-inflammatory cytokines and accelerates the wound healing. Therefore, identifying molecules that have the ability to modulate the inflammasome assembly and activation, or inflammasome-mediated products, can reduce fibrosis and promote wound healing(Artlett, 2013) Chen et al (2022). investigated the early inflammatory response to titanium screws in bone, and concluded that the administration of ipriflavone, a natural isoflavone, decreased the activation of the NLRP3 inflammasome in macrophages.…”

Endowing Polyetheretherketone with Anti‐Infection and Immunomodulatory Properties through Guanidination Carbon Dots Modification to Promote Osseointegration in Diabetes with MRSA Infection

“…Additionally, the expression of the NLRP3 inflammasome, which is known to negatively affect bone healing, was also examined. [ 35 ] As shown in Figure A–D, the SP@GCDs (−) group demonstrated the most effective suppression of pro‐inflammatory markers (TNF‐ α, IL‐6, IL‐1β) and NLRP3. Although the SP@GCDs (+) group was not as good as the SP@GCDs (−) group, it still significantly inhibited the expression of TNF‐ α, IL‐6, IL‐1 β, and NLRP3.…”

The role of mitochondria in the peri‐implant microenvironment

“…Adiponectin, a fat-derived adipokine with anti-diabetic efficacy, can reverse ROS overproduction and alleviate mitochondrial damage by activating AMPK, thus reversing osteoblast impairment and improving the osteointegration (Hu et al, 2017). Chen, Li, Shi et al (2022) revealed that ipriflavone reduced inflammasome activation in macrophages by decreasing mROS and thus ameliorated the host inflammatory response and promoted early bone healing. Resveratrol can also increase mitochondrial biogenesis and reduce mROS and thus improve mitochondrial function (Ma et al, 2017;Ungvari et al, 2011).…”

“…There is a large literature on the roles of mROS in cellular physiological functions, including cell proliferation, migration, and differentiation (Blajszczak & Bonini, 2017;Chen, Li, Shi et al, 2022;Wang, Fu et al, 2021;Wang, Yang et al, 2020).…”