Neuroimmune changes underscore pain-associated behaviors and disc herniations in SM/J mice

Novais, E. J.; Ottone, O. K.; Brown, E. V.; Madhu, V.; Tran, V. A.; Dighe, A. S.; Solga, M. D.; Manchel, A.; Lepore, A. C.; Risbud, M. K.

doi:10.1101/2024.02.23.581794

bioRxiv · 10.1101/2024.02.23.581794

Neuroimmune changes underscore pain-associated behaviors and disc herniations in SM/J mice

Novais, E. J.·Ottone, O. K.·Brown, E. V.·Madhu, V.·Tran, V. A.·Dighe, A. S.·Solga, M. D.·Manchel, A.·Lepore, A. C.·Risbud, M. K.

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Abstract

There are no appropriate mouse models to study the pathophysiology of spontaneous disc herniations and associated pain pathology. We demonstrate that SM/J mice show a high incidence of age-associated lumbar disc herniations with neurovascular innervations. Transcriptomic comparisons of the SM/J annulus fibrosus with human tissues showed shared pathways related to immune cell activation and inflammation. Notably, aged SM/J mice showed increased pain sensitization and neuroinflammatory signatures associated with altered extracellular matrix regulation in the DRGs and spinal cord. There were increased T cells in the vertebral marrow, and CyTOF analysis showed increased splenic CD8+ T cells, nonspecific activation of CD8+ memory T cells, and enhanced IFN-{gamma} production in the myeloid compartment. ScRNA-seq of PBMCs in SM/J showed more B cells, with lower proportions of T cells, monocytes, and granulocytes. This study identifies SM/J mice as a clinically-relevant model to study the pathophysiology of spontaneous disc herniations and highlights a causative axis for chronic discogenic pain with novel contributors from the primary lymphoid organs (spleen and vertebral marrow), circulation, and the nervous system. One-Sentence SummaryThe novel SM/J mouse model shows a neuroimmune axis drives chronic back pain, a leading cause of years lived with disability.

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Novais, E. J., Ottone, O. K., Brown, E. V., Madhu, V., Tran, V. A., Dighe, A. S., Solga, M. D., Manchel, A., Lepore, A. C., Risbud, M. K.. 2024-02-24. Neuroimmune changes underscore pain-associated behaviors and disc herniations in SM/J mice. https://doi.org/10.1101/2024.02.23.581794

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