Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy

Abstract

Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is characterized by neuropathic pain and small-fiber degeneration, accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability and loss of their axons within the skin. The molecular mechanisms underlying DRG nociceptor hyperexcitability and small-fiber degeneration in PDN are unknown. We hypothesize that chemokine CXCL12/CXCR4 signaling is central to this mechanism, as we have shown that CXCL12/CXCR4 signaling is necessary for the development of mechanical allodynia, a pain hypersensitivity behavior common in PDN. Focusing on DRG neurons expressing the sodium channel Nav1.8, we applied transgenic, electrophysiological, imaging, and chemogenetic techniques to test this hypothesis. In the high-fat diet mouse model of PDN, we were able to prevent and reverse mechanical allodynia and small-fiber degeneration by limiting CXCR4 signaling or neuronal excitability. This study reveals that excitatory CXCR4/CXCL12 signaling in Nav1.8-positive DRG neurons plays a critical role in the pathogenesis of mechanical allodynia and small-fiber degeneration in a mouse model of PDN. Hence, we propose that targeting CXCR4-mediated DRG nociceptor hyperexcitability is a promising therapeutic approach for disease-modifying treatments for this currently intractable and widespread affliction.

Inflammatory Macrophages in the Sciatic Nerves Facilitate Neuropathic Pain Associated with Type 2 Diabetes Mellitus

“…In our results, the induction of mechanical allodynia did not completely correlate to the time course of macrophage accumulation. Nevertheless, the induction period is consistent with other reports using similar HFD feeding models (Jayaraj et al, 2018). These lines of evidence suggest that the molecular mechanisms of mechanical allodynia in the induction phase might be different from those in the maintenance phase.…”

“…Among the variety of basic approaches used to uncover the pathogenesis of complications in T2DM, high-fat diet (HFD)-induced diabetes with obesity has proved to be the most popular experimental model in rodents, being closely correlated with the known pathology of T2DM (Heydemann, 2016). For example, T2DM experimental rodent models induced by HFD feeding and patients with T2DM present hyperexcitability and spontaneous activity of primary sensory neurons reflecting the typical symptoms of neuropathic pain, such as hyperalgesia and allodynia (Baron et al, 2009;Menichella et al, 2014;Jayaraj et al, 2018). Therefore, HFD feeding is also a useful approach to investigate the molecular background of T2DM-related neuropathic pain in rodents.…”

Neuronal LXR Regulates Neuregulin-1 Expression and Sciatic Nerve-Associated Cell signaling

“…Previous studies including ours have shown that Nav1.8 expressing neurons in the DRG play a critical role in the pathogenesis of WD-associated neuropathy 16,32 . To specifically test, the effect of WD or of saturated fatty acids on Nrg1 expressed in sensory neurons of the DRG, we directly purified mRNA in translation (associated with ribosomes) from DRG sensory neurons.…”

“…Others and we identified that WD-feeding led to peripheral neuropathy affecting the sensory neurons and their associated SC 16,32 . Previous reports demonstrated that modification in SC metabolism in the sciatic nerve were strongly linked to neuropathy phenotype in obesity 3 .…”

“…Previous studies from others and our group showed that signaling pathway in the neurons of the DRG is disrupted inducing cellular stress 16,32,38,47 . Our previous data showed that activation of LXR might regulate lipid metabolism in sensory neurons of the DRG in vivo to blunt the WD-induced cellular stress in sensory neurons of the DRG 16 .…”