CXCL16 mediates nociception and inflammation in murine post-traumatic osteoarthritis

Lammlin, L.; Redding, S.; Knights, A. J.; Mohan, A.; Newton, M. D.; Bergman, R. F.; Smith, I. J.; Howser, S. C.; Gonzalez-Nolde, S.; Rzeczycki, P. M.; Adamczyk, N. S.; Miller, R. E.; Maerz, T.

doi:10.1101/2025.04.10.647297

bioRxiv · 10.1101/2025.04.10.647297

CXCL16 mediates nociception and inflammation in murine post-traumatic osteoarthritis

Lammlin, L.·Redding, S.·Knights, A. J.·Mohan, A.·Newton, M. D.·Bergman, R. F.·Smith, I. J.·Howser, S. C.·Gonzalez-Nolde, S.·Rzeczycki, P. M.·Adamczyk, N. S.·Miller, R. E.·Maerz, T.

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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 SummaryCXCL16 regulates synovial inflammation and mediates joint nociception via CXCR6, highlighting its potential as a therapeutic target for post-traumatic osteoarthritis.

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Lammlin, L., Redding, S., Knights, A. J., Mohan, A., Newton, M. D., Bergman, R. F., Smith, I. J., Howser, S. C., Gonzalez-Nolde, S., Rzeczycki, P. M., Adamczyk, N. S., Miller, R. E., Maerz, T.. 2025-04-16. CXCL16 mediates nociception and inflammation in murine post-traumatic osteoarthritis. https://doi.org/10.1101/2025.04.10.647297

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