Abstract
Neuropathic pain caused by peripheral nerve injuries significantly affects sensory perception and quality of life. Accumulating evidence strongly link cholesterol with development and progression of Obesity and Diabetes associated-neuropathies. However, the exact mechanisms of how cholesterol/lipid metabolism in peripheral nervous system (PNS) contributes to the pathogenesis of neuropathy remains poorly understood. Dysregulation of LXR pathways have been identified in many neuropathic models. The cholesterol sensor, LXR α/β, expressed in sensory neurons are necessary for proper peripheral nerve function. Deletion of LXR α/β from sensory neurons lead to pain-like behaviors. In this study, we identified that LXR α/β expressed in sensory neurons regulates neuronal Neuregulin 1 (Nrg1), protein involved in cell-cell communication. Using in vivo cell-specific approaches, we observed that loss of LXR from sensory neurons altered genes in non-neuronal cells located in the sciatic nerve (potentially representing Schwann cells (SC)). Our data suggest that neuronal LXRs may regulate non-neuronal cell function via a Nrg1-dependent mechanism. The decrease in Nrg1 expression in DRG neurons of WD-fed mice may suggest an altered Nrg1-dependent neuron-SC communication in Obesity. The communication between neurons and non-neuronal cells such as SC could be a new biological pathway to study and understand the molecular and cellular mechanism underlying Obesity-associated neuropathy and PNS dysfunction.
Highlights
In the peripheral system, neurons and their axons are associated with non-neuronal cells and they have a high interdependent relationship i.e., damage to one cell type leads to pathophysiological changes in the other
Sciatic nerves from normal chow (NC)- and WD-fed mice were dissected, total RNA was purified and only samples with high quality test were subjected to RNA sequencing (Fig. 1A)
RNA sequencing (RNA-seq) analysis identified 4,166 differentially regulated genes between NC and WD-fed mice sciatic nerves (Fig. 1B–D) (n = 2 biological replicates, 4 sciatic nerve pooled per replicate)
Summary
Neurons and their axons are associated with non-neuronal cells and they have a high interdependent relationship i.e., damage to one cell type leads to pathophysiological changes in the other. The SC population is heterogeneous since some SC produce myelin and others do not, in all cases reported, SC are crucial for normal PNS function and repair[23,24,25]. These specific roles of different SC population are understudied in vivo because markers defining specific SC population are unknown. Our in vivo data uncovered a unique pathway involving neurons/non-neuronal cell communication potentially involved in neuropathy induced by type II diabetes and Obesity
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