Decoupling musculoskeletal damage from antiviral control: the NLRP3 inflammasome in arthritogenic alphavirus infection.

Mosquito-borne arthritogenic alphaviruses, including chikungunya virus (CHIKV), Ross River virus (RRV), and Mayaro virus (MAYV), cause acute febrile polyarthralgia and can leave a substantial proportion of patients with persistent or relapsing musculoskeletal disease. In many cohorts, chronic arthritis continues after systemic viremia has declined, suggesting that late tissue pathology is sustained largely by host inflammatory programs rather than by ongoing productive viral replication. This Mini Review examines the NLRP3 inflammasome as a pathogenic node linking viral danger sensing to chronic joint and bone damage, and considers whether this pathway can be targeted to reduce tissue injury while preserving antiviral control. Across CHIKV, RRV, and MAYV models, pattern-recognition receptor signaling provides NF-κB-dependent priming of NLRP3, pro-IL-1β, and pro-IL-18, whereas K+ efflux, mitochondrial stress, reactive oxygen species, and lysosomal disruption promote NLRP3-ASC-caspase-1 assembly in musculoskeletal niches. The resulting IL-1β and IL-18 release and, in selected contexts, pyroptosis-associated amplification propagate inflammatory signaling across monocytes/macrophages, fibroblast-like synoviocytes, osteoblasts, and osteoclast-lineage cells, thereby promoting synovitis, myositis, osteoclastogenesis, and bone loss. Pharmacological and genetic studies indicate partial phenotypic separation between tissue damage and viral control, as NLRP3 inhibition or IL-1 receptor blockade can attenuate musculoskeletal pathology with limited effects on viral burden in available preclinical models. We highlight three priorities for translation: defining post-acute therapeutic windows, stratifying patients using inflammasome and bone-turnover biomarkers, and incorporating bone-centered endpoints such as micro-computed tomography and osteoclast histomorphometry.