{"doi":"10.1101/2025.04.10.647297","title":"CXCL16 mediates nociception and inflammation in murine post-traumatic osteoarthritis","abstract":"This study investigates the role of the chemokine CXCL16 and its receptor, CXCR6, in post-traumatic osteoarthritis (PTOA) and joint nociception, highlighting the potential of targeting the CXCL16-CXCR6 axis for therapeutically managing joint inflammation and pain. 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. One Sentence Summary: CXCL16 regulates synovial inflammation and mediates joint nociception via CXCR6, highlighting its potential as a therapeutic target for post-traumatic osteoarthritis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557621,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1457462,"name":"S Redding","orcid":"0009-0002-3633-411X","position":1,"is_corresponding":false},{"id":467867,"name":"Alexander J. Knights","orcid":"0000-0001-8402-2212","position":2,"is_corresponding":false},{"id":1384294,"name":"Anish Mohan","orcid":null,"position":3,"is_corresponding":false},{"id":1150883,"name":"Michael D. Newton","orcid":"0000-0003-1262-0613","position":4,"is_corresponding":false},{"id":845963,"name":"Rachel Bergman","orcid":"0000-0002-6702-8871","position":5,"is_corresponding":false},{"id":1457765,"name":"Isabelle J. Smith","orcid":null,"position":6,"is_corresponding":false},{"id":1431854,"name":"Scarlet Howser","orcid":null,"position":7,"is_corresponding":false},{"id":1276755,"name":"Sofia Gonzalez-Nolde","orcid":"0009-0001-6801-1270","position":8,"is_corresponding":false},{"id":845962,"name":"Phillip Rzeczycki","orcid":"0000-0002-2149-2249","position":9,"is_corresponding":false},{"id":760063,"name":"Natalie S. Adamczyk","orcid":"0000-0002-6462-0271","position":10,"is_corresponding":false},{"id":353852,"name":"Rachel E. Miller","orcid":"0000-0002-4486-5757","position":11,"is_corresponding":false},{"id":774769,"name":"Tristan Maerz","orcid":"0000-0002-4523-6012","position":12,"is_corresponding":false},{"id":845960,"name":"Lindsey Lammlin","orcid":"0000-0003-4126-8292","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:55:17.435961Z","pmid":"41394661","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}