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

Abstract

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.

Sex- and cell-dependent contribution of peripheral high mobility group box 1 and TLR4 in arthritis-induced pain

“…Of note, recent work also reported the contribution of neuronal TLR4 in pain-related behavior after nerve injury in both male and female mice. 52 Thus, although HMGB1 is pronociceptive in both sexes and neuronal TLR4 seems to contribute to this, there may still be mechanistic aspects associated with differential actions on inflammatory cells that differ between sexes, in particular because it has been postulated that in the spinal cord, different nonneuronal cells contribute to sensitization in male and female mice, with microglia dominating this process in males and T cells in females. 43 Recently, we also reported that spinal glial inhibition reversed mechanical hypersensitivity in male, but not female, mice in the postinflammatory phase of the CAIA model.…”

Utility of LysM-cre and Cdh5-cre Driver Mice in Retinal and Brain Research: An Imaging Study Using tdTomato Reporter Mouse

“…45 Lysozyme has also been recently shown to be involved in neuropathic pain. 46 These diverse actions could explain the purpose of LysM expression by adult neurons.…”

Toll-Like Receptor 4 in the Rat Caudal Medulla Mediates Tooth Pulp Inflammatory Pain

“…Sun et al (2015) also used LPS-RS as a TLR4 antagonist in their SMR study, but they did not report if this antagonist had any effect on TLR4 expression. While LPS-RS is considered an LPS antagonist, its mechanism of action may not be related to TLR4 expression, but rather to the prevention of TLR4 signaling, which could also involve other molecules such as heat shock proteins (Cognasse et al, 2015;Gao and Li, 2016;Yadav and Surolia, 2019). Further studies in orofacial pain models are needed to address these possibilities.…”