NLRP3 Inflammasome Negatively Regulates RANKL-Induced Osteoclastogenesis of Mouse Bone Marrow Macrophages but Positively Regulates It in the Presence of Lipopolysaccharides

Abstract

In inflammatory bone diseases such as periodontitis, the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome accelerates bone resorption by promoting proinflammatory cytokine IL-1β production. However, the role of the NLRP3 inflammasome in physiological bone remodeling remains unclear. Here, we investigated its role in osteoclastogenesis in the presence and absence of lipopolysaccharide (LPS), a Gram-negative bacterial component. When bone marrow macrophages (BMMs) were treated with receptor activator of nuclear factor-κB ligand (RANKL) in the presence of NLRP3 inflammasome inhibitors, osteoclast formation was promoted in the absence of LPS but attenuated in its presence. BMMs treated with RANKL and LPS produced IL-1β, and IL-1 receptor antagonist inhibited osteoclastogenesis, indicating IL-1β involvement. BMMs treated with RANKL alone produced no IL-1β but increased reactive oxygen species (ROS) production. A ROS inhibitor suppressed apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) speck formation and NLRP3 inflammasome inhibitors abrogated cytotoxicity in BMMs treated with RANKL, indicating that RANKL induces pyroptotic cell death in BMMs by activating the NLRP3 inflammasome via ROS. This suggests that the NLRP3 inflammasome promotes osteoclastogenesis via IL-1β production under infectious conditions, but suppresses osteoclastogenesis by inducing pyroptosis in osteoclast precursors under physiological conditions.

Dental Pulp Stem Cell-Derived Exosomes Regulate Anti-Inflammatory and Osteogenesis in Periodontal Ligament Stem Cells and Promote the Repair of Experimental Periodontitis in Rats

“… 51 Pro-inflammatory macrophages can elevate local expression of RANKL, which promotes osteoclast differentiation in the periodontium. 52 , 53 In contrast, anti-inflammatory macrophages are involved in inflammation resolution and tissue regeneration via the secretion of anti-inflammatory mediators. 54 In addition, anti-inflammatory macrophages contribute to the exocytosis of apoptotic osteoblasts and mediate bone formation.…”

Programmed cell death of periodontal ligament cells

“…In inflammatory bone diseases such as periodontitis, the NLRP3 inflammasome promotes bone resorption by inducing the production of the pro-inflammatory cytokine IL-1β. Studies have investigated its role in osteoclastogenesis in the presence and absence of LPS and have found that the NLRP3 inflammasome promotes osteoclastogenesis via IL-1β during infection, but inhibits osteoclastogenesis by inducing pyroptosis of osteoclast precursor cells under physiological conditions (Alam et al, 2022).…”

Emerging factors affecting peri‐implant bone metabolism

“…Under infectious conditions, inflammasome activation promoted bone loss due to induced osteoclast formation mediated by IL‐1B production, probably to eliminate injured bone or pathogens around bone. Meanwhile, under physiological conditions, the inflammasome seemed to inhibit osteoclast formation via pyroptosis and helped to maintain bone homeostasis 213 . Moreover, activation of the inflammasome stimulates M1 polarization 196 .…”