Context-dependent roles of the NLRP3 inflammasome in osteomyelitis and strategies for precision modulation
TL;DR
It is proposed that future NLRP3-targeted therapy for osteomyelitis should shift from “non-specific anti-inflammation” to “bone immune reprogramming”—stratified intervention based on infection stage, cell type, and inflammasome activation level, integrating NLRP3 modulation with antibacterial, anti-biofilm, anti-pyroptotic, and osteogenic-promoting strategies.
Abstract
Osteomyelitis is an inflammatory bone disease caused by pathogen infection, characterized by persistent infection, bone destruction, and impaired repair. Its refractoriness stems from the interplay between pathogen persistence and dysregulated host immune responses within the unique bone microenvironment. As a critical sensor of innate immunity, the NLRP3 inflammasome integrates pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), playing a pivotal regulatory role in the initiation and chronicity of osteomyelitis through caspase-1 activation, maturation and release of IL-1β and IL-18, and Gasdermin D (GSDMD)-mediated pyroptosis. This review systematically summarizes the activation mechanisms of the NLRP3 inflammasome within the bone immune microenvironment of osteomyelitis and its functions across multiple cell lineages. The local osteomyelitis microenvironment provides sustained NLRP3 activation signals through pathogen components, host damage signals, and bone matrix degradation products. Various cells, including macrophages, contribute to inflammatory amplification, enhanced bone resorption, or impaired repair via NLRP3-related pathways, forming a multi-layered pathological network through intercellular crosstalk. Mechanistically, four key axes operate: the IL-1β/receptor activator of nuclear factor-κB ligand (RANKL)/osteoclast axis driving infectious bone resorption; the GSDMD/pyroptosis/DAMPs axis sustaining a self-amplifying inflammatory loop; the reactive oxygen species (ROS)/mitochondria/autophagy axis providing the metabolic basis for persistent NLRP3 activation; and the osteoblast inhibition axis explaining post-infection repair failure. Notably, NLRP3 exhibits context-dependent roles in osteomyelitis—it may participate in antimicrobial defense during early infection, while in the chronic phase it primarily drives bone destruction and inadequate repair. Furthermore, Staphylococcus aureus can evade host defenses by attenuating NLRP3-mediated responses. Therapeutically, direct NLRP3 small-molecule inhibitors, caspase-1 inhibitors, GSDMD/pyroptosis inhibitors, IL-1β/IL-1R blockade, and mesenchymal stem cell (MSC)-derived exosome therapy all show potential value. However, the risk of systemic immunosuppression necessitates combining these strategies with adequate debridement and pathogen control. Local drug delivery systems, which achieve effective concentrations at the lesion while reducing systemic exposure, represent a more translationally promising direction. We propose that future NLRP3-targeted therapy for osteomyelitis should shift from “non-specific anti-inflammation” to “bone immune reprogramming”—stratified intervention based on infection stage, cell type, and inflammasome activation level, integrating NLRP3 modulation with antibacterial, anti-biofilm, anti-pyroptotic, and osteogenic-promoting strategies. This paradigm shift aims to transition from simple infection control to the reconstruction of a reparative bone immune microenvironment.