Lysozyme elicits pain during nerve injury by neuronal Toll-like receptor 4 activation and has therapeutic potential in neuropathic pain

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Science Translational Medicine  07 Aug 2019:
Vol. 11, Issue 504, eaav4176
DOI: 10.1126/scitranslmed.aav4176

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Bacteriolytic pain

Neuropathic pain is a debilitating condition originating from nerve damage. The current treatments have limited efficacy or are associated with serious side effects. Toll-like receptor 4 (TLR4) activation promotes neuropathic pain; however, the molecular pathway responsible for TLR4 activation is unclear. Using rodent models and human tissue, Yadav et al. now show that the endogenous bacteriolytic enzyme lysozyme is up-regulated upon nerve injury in both rodents and humans. Lysozyme acts as TLR4 activator in sensory neurons, promoting chronic pain in rodents. Moreover, the lysozyme administration in spinal cord of healthy rats was sufficient to cause neuropathic pain by increasing neuronal excitability.


The role of neuronal Toll-like receptor 4 (TLR4) in nerve injury is being pursued actively. However, the endogenous activation of neuronal TLR4 during neuroinflammation, in absence of the participation of glial TLR4, remains elusive. Here, we identified lysozyme as an endogenous activator of neuronal TLR4 signaling during nerve injury. Upon nerve injury, enhanced expression of lysozyme promoted neuronal hyperexcitability and neuropathic pain. Injections of lysozyme in healthy rats increased their mechanical and thermal pain sensitivity. Likewise, infusion of spinal cord slices with lysozyme increased neuronal excitability typical of neuropathic pain. Our results also showed that lysozyme activated excitability of both Aδ- and C-fibers. Thus, in addition to the discovery of lysozyme as an endogenous ligand for regulating neuronal TLR4 signaling, this study also lays the foundation of our understanding of its role in nervous system pathologies, providing multiple avenues for treating neuroinflammation.

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