{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:15:53Z","timestamp":1783577753671,"version":"3.55.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["2026AFB637"],"award-info":[{"award-number":["2026AFB637"]}],"id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>\n                    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-\u03baB-dependent priming of NLRP3, pro-IL-1\u03b2, and pro-IL-18, whereas K\n                    <jats:sup>+<\/jats:sup>\n                    efflux, mitochondrial stress, reactive oxygen species, and lysosomal disruption promote NLRP3\u2013ASC\u2013caspase-1 assembly in musculoskeletal niches. The resulting IL-1\u03b2 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.\n                  <\/jats:p>","DOI":"10.3389\/fcimb.2026.1880650","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:35:19Z","timestamp":1783575319000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoupling musculoskeletal damage from antiviral control: the NLRP3 inflammasome in arthritogenic alphavirus infection"],"prefix":"10.3389","volume":"16","author":[{"given":"Fahu","family":"Yuan","sequence":"first","affiliation":[{"name":"School of Medicine, Jianghan University","place":["Wuhan, China"]},{"name":"State-owned Assets and Laboratory Management Office, Jianghan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangyuan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, Jianghan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6040","DOI":"10.1073\/pnas.1318859111","article-title":"Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss","volume":"111","author":"Chen","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1038\/s41564-017-0015-4","article-title":"Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation","volume":"2","author":"Chen","year":"2017","journal-title":"Nat. Microbiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1093\/infdis\/jiq042","article-title":"Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor","volume":"203","author":"Chow","year":"2011","journal-title":"J. Infect. Dis."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007934","article-title":"The NLRP3 inflammasome is involved with the pathogenesis of Mayaro virus","volume":"15","author":"de Castro-Jorge","year":"2019","journal-title":"PloS Pathog."},{"key":"B5","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/s41579-025-01177-8","article-title":"Chikungunya virus and other emerging arthritogenic alphaviruses","volume":"23","author":"de Souza","year":"2025","journal-title":"Nat. Rev. Microbiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/nrd3800","article-title":"Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases","volume":"11","author":"Dinarello","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006748","article-title":"Inflammatory monocytes mediate control of acute alphavirus infection in mice","volume":"13","author":"Haist","year":"2017","journal-title":"PloS Pathog."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1942","DOI":"10.1093\/infdis\/jiy129","article-title":"NLRP3 inflammasome activation mediates Zika virus-associated inflammation","volume":"217","author":"He","year":"2018","journal-title":"J. Infect. Dis."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20133328","article-title":"The NLRP3 inflammasome: an overview of mechanisms of activation and regulation","volume":"20","author":"Kelley","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e270","DOI":"10.1016\/S2665-9913(20)30065-5","article-title":"Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial","volume":"2","author":"Kl\u00fcck","year":"2020","journal-title":"Lancet Rheumatol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1086\/587841","article-title":"Macrophage-derived proinflammatory factors contribute to the development of arthritis and myositis after infection with an arthrogenic alphavirus","volume":"197","author":"Lidbury","year":"2008","journal-title":"J. Infect. Dis."},{"key":"B12","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.immuni.2020.06.017","article-title":"Cytokine storms: understanding COVID-19","volume":"53","author":"Mangalmurti","year":"2020","journal-title":"Immunity"},{"key":"B13","doi-asserted-by":"publisher","first-page":"E1530","DOI":"10.1073\/pnas.1716095115","article-title":"OLT1177, a \u03b2-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation","volume":"115","author":"Marchetti","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B14","doi-asserted-by":"publisher","first-page":"46923","DOI":"10.1074\/jbc.M207847200","article-title":"Alphavirus 6K proteins form ion channels","volume":"277","author":"Melton","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/d41573-019-00086-9","article-title":"NLRP3 inhibitors stoke anti-inflammatory ambitions","volume":"18","author":"Mullard","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"B16","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1074\/jbc.M116.756379","article-title":"PB1-F2 peptide derived from avian influenza A virus H7N9 induces inflammation via activation of the NLRP3 inflammasome","volume":"292","author":"Pinar","year":"2017","journal-title":"J. Biol. Chem."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.780641","article-title":"Soluble urokinase plasminogen activator receptor (suPAR) as a biomarker of systemic chronic inflammation","volume":"12","author":"Rasmussen","year":"2021","journal-title":"Front. Immunol."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004104","article-title":"Long-term arthralgia after Mayaro virus infection correlates with sustained pro-inflammatory cytokine response","volume":"9","author":"Santiago","year":"2015","journal-title":"PloS Negl.Trop. Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.celrep.2016.06.028","article-title":"Identification of Zika virus and Dengue virus dependency factors using functional genomics","volume":"16","author":"Savidis","year":"2016","journal-title":"Cell Rep."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00352","article-title":"Dengue virus serotype 2 and its non-structural proteins 2A and 2B activate NLRP3 inflammasome","volume":"11","author":"Shrivastava","year":"2020","journal-title":"Front. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1038\/nrrheum.2012.64","article-title":"Arthritogenic alphaviruses--an overview","volume":"8","author":"Suhrbier","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41577-019-0165-0","article-title":"The NLRP3 inflammasome: molecular activation and regulation to therapeutics","volume":"19","author":"Swanson","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"750","DOI":"10.3201\/eid2204.151502","article-title":"Sustained elevated cytokine levels during recovery phase of Mayaro virus infection","volume":"22","author":"Tappe","year":"2016","journal-title":"Emerg. Infect. Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/s41467-017-02645-3","article-title":"Zika virus infection induces host inflammatory responses by facilitating NLRP3 inflammasome assembly and interleukin-1\u03b2 secretion","volume":"9","author":"Wang","year":"2018","journal-title":"Nat. Commun."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1002\/art.40856","article-title":"Inhibition of interleukin-1\u03b2 signaling by Anakinra demonstrates a critical role of bone loss in experimental arthritogenic alphavirus infections","volume":"71","author":"Wolf","year":"2019","journal-title":"Arthritis Rheumatol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1038\/s41564-026-02303-9","article-title":"Chikungunya virus persists in joint-associated macrophages and promotes chronic disease in mice","volume":"11","author":"Zarrella","year":"2026","journal-title":"Nat. Microbiol."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00211","article-title":"NLRP3 inflammasome-a key player in antiviral responses","volume":"11","author":"Zhao","year":"2020","journal-title":"Front. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"14040","DOI":"10.1074\/jbc.RA120.015036","article-title":"Impaired NLRP3 inflammasome activation\/pyroptosis leads to robust inflammatory cell death via caspase-8\/RIPK3 during coronavirus infection","volume":"295","author":"Zheng","year":"2020","journal-title":"J. Biol. Chem."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1880650\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:35:20Z","timestamp":1783575320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1880650\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":28,"alternative-id":["10.3389\/fcimb.2026.1880650"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2026.1880650","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]},"article-number":"1880650"}}