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Following joint injury in mice, the CXCL16-CXCR6 signaling axis is activated in synovium, driven by synovial fibroblasts and macrophages. Human OA synovium also exhibited increased CXCL16 and CXCR6 gene expression. CXCL16 stimulated a pro-inflammatory response in fibroblasts and macrophages, contrasting with an anti-inflammatory response observed in mesenchymal progenitor cells. In mice, repeated intra-articular CXCL16 injections induced histological synovitis and sex-dependent activation of inflammatory and fibrotic transcriptional programs in synovium. Repeated CXCL16 joint injections also induced knee hyperalgesia, which was mitigated by co-administration of the CXCR6 antagonist, ML339. A single intra-articular injection of CXCL16 induced acute knee hyperalgesia as early as 30 minutes post-injection, which was completely abrogated by ML339 co-treatment, suggesting direct CXCL16 binding to nociceptor-expressed CXCR6. In a murine PTOA model, systemic CXCR6 antagonism with ML339 alleviated knee hyperalgesia and altered circulating immune cell profiles. Direct stimulation of mouse dorsal root ganglion-derived nociceptive neurons with CXCL16 induced rapid calcium signaling, which was abolished by co-treatment with ML339. These findings establish CXCL16 as a regulator of joint inflammation and identifies the CXCL16-CXCR6 binding mechanism as key in mediating pain-related behaviors and nociceptor activation, offering a therapeutic target for PTOA-related inflammation and pain management.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>CXCL16 regulates synovial inflammation and mediates joint nociception via CXCR6, highlighting its potential as a therapeutic target for post-traumatic osteoarthritis.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.04.10.647297","type":"posted-content","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T11:52:10Z","timestamp":1745409130000},"source":"Crossref","is-referenced-by-count":0,"title":["CXCL16 mediates nociception and inflammation in murine post-traumatic osteoarthritis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4126-8292","authenticated-orcid":false,"given":"Lindsey","family":"Lammlin","sequence":"first","affiliation":[{"name":"ETH Z\u00fcrich, Z\u00fcrich, Switzerland"},{"name":"Department of Orthopaedic Surgery, University of Michigan; Ann Arbor, Michigan, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Redding","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Michigan; Ann Arbor, Michigan, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8402-2212","authenticated-orcid":false,"given":"Alexander J.","family":"Knights","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Michigan; Ann Arbor, Michigan, United States"},{"name":"Washington University St. Louis, St. Louis, 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