Background & Aims

Upon cellular stress, including aging and injury, cells can enter a complex state called ‘cellular senescence’ in which they cease division, resist apoptosis, and express a pro-inflammatory ‘senescence-associated secretory phenotype’ (SASP). Senescence has been extensively studied in mitotic cells given its original hallmark feature of cell-cycle arrest, leaving senescence of post-mitotic cells underexplored. Recently, markers of senescence have been reported in post-mitotic neurons, yet they are incompletely characterized and their function is not understood.

Methods

We performed spared nerve injury (SNI) in young (3-months) and aged (22-24 months) C57BL/6J mice, which produces long-lasting neuropathic pain in the ipsilateral hindpaw. We investigated neuronal expression of multiple senescence markers (p21, p16, IL6) using RNAscope as well as SA-?-galactosidase activity in the dorsal root ganglion (DRG) with age and after injury. We further established the electrophysiological properties of neurons which expressed senescence markers and evaluated pain behaviors following elimination of these senescent cells in vivo. Finally, we assayed senescence marker expression in human DRG neurons with age to clarify the translational relevance.

Results

We show that mouse primary sensory neurons in the DRG senesce with age, and after peripheral nerve injury as they co-express multiple markers of senescence (p21, p16) with the SASP factor and known pain mediator, IL6. A subset of these senescent IL6-expressing neurons were Trpv1-positive nociceptive neurons, which persisted in the DRG long-term post-injury. Further, electrophysiological characterization of neurons expressing senescence markers revealed high-firing and nociceptor-like phenotypes within these populations. Pharmacological targeting of senescent neurons in mice resulted in improved allodynia and weight bearing on the injured hindlimb, suggesting these cells contribute to hypersensitivity post-injury. Analysis of human DRG revealed an age-related increase in neuronal expression of senescence markers p21 and p16, along with SASP factor IL6, validating the translational relevance of neuronal senescence.

Conclusions

Overall, a potential mechanism of nerve injury-induced chronic pain may be the generation and persistence of senescent primary sensory neurons in the DRG, enhanced by age, that produce downstream SASP factors including pain-producing cytokine IL6. Funding: 1R21AG075622.

References

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Presenting Author

Lauren Donovan

Poster Authors

LAUREN DONOVAN

PhD

Stanford University

Lead Author

Topics

  • Mechanisms: Biological-Molecular and Cell Biology