Chronic neuroinflammation in the peripheral/central nervous system is important for the molecular basis of neuropathic pain. In particular, roles of macrophage and microglia have been well demonstrated. In this study, we evaluated the region, time, and sex-dependent effects of macrophages/microglia on neuropathic pain using mice that can induce Gi-DREADD driven by macrophages/microglia-specific cx3cr1 promoter (CX3CR1-hM4Di). Neuropathic pain model mice were generated by partial sciatic nerve ligation (PSL) or paclitaxel treatment, and mechanical allodynia was evaluated using von Frey test.
Type 2 diabetes mellitus (T2DM) is a common metabolic disease results in long-term complications associated with the dysfunction of nervous system, and more than 50% of patients eventually experience neuropathic pain. Given that peripheral neuroinflammation driven by inflammatory macrophages plays a pivotal role in the pathogenesis of neuropathic pain in rodent models of neuropathic pain following peripheral nerve injury, it is pivotal to determine whether inflammatory macrophages contribute to the pathogenesis of neuropathic pain caused by T2DM in mice.
Cumulative evidences have shown the importance of ER-stress in pathology of neurodegenerative diseases, such as Alzheimer's disease, Amyotrophic lateral sclerosis, etc. To elucidate the pathogenesis of neurodegenerative diseases from the viewpoint of ER-stress, we screened the altered genes in SK-N-SH cells under the condition of tunicamycin-induced ER-stress by the gene fishing method. As the result, we found that Protein arginine N-methyltransferase 1 (PRMT1) is up-regulated in SK-N-SH cells under ER-stress. Based on this result, we examined the effects of PRMT1 knockdown on the ER-stress related pathway and organelle, and found that PRMT1 knockdown cells showed the abnormal Golgi formation and increased UPR. To elucidate the mechanism of these alterations, we screened the methylated proteins as substrates of PRMT1 under ER-stress condition by immunoprecipitation-mass spectroscopy, and identified Scy1-like protein 1 (Scyl1). Scyl1, a member of the Scy1-like family of catalytically inactive protein kinases, was recently reported to function in retrograde COPI-mediated intracellular transport. Interestingly, Scyl1 has also been identified as a gene product that is lost in an animal model of motor neuron disease, the muscle-deficient mouse. In the motor neuron of the above model animal, the protein circulation system between ER and Golgi apparatus was abnormal due to dysfunction of COPI transport. In consequence, UPR may be accerelated. Thus, we present the effect of Scyl1 arginine methylation on the COPI vesicle transport. This study provides novel insights into the pathogenesis of neurodegenerative diseases caused by ER stress.
Abstract Inflammation mediated by the crosstalk between leukocytes and resident tissue cells is crucial for the maintenance of homeostasis. Because chemokine ligands and receptors, which recruit a variety of leukocytes, are widely distributed among tissues, it is important to understand the mechanisms regulating inflammatory disease. Chemokines such as CC-chemokine ligand 2 (CCL2) amplify and maintain inflammation through chemokine-cytokine networks after the recruitment of circulating leukocytes. Chemokine-dependent nonresolving inflammation occurs in the peripheral and central nervous systems, and underlies several intractable diseases, including cancer and neuropathic pain. The chronic upregulation of chemokines is often mediated by epigenetic mechanisms consisting of DNA methylation, histone modification, and nucleosome positioning. In particular, histone acetylation and methylation have been shown to play important roles in the upregulation of chemokine expression. In addition to CCL2, several other chemokines strongly contribute to neuropathic pain through epigenetic induction. Consequently, targeting epigenetic changes may have therapeutic potential for nonresolving inflammatory diseases such as neuropathic pain. Further research into the epigenetics of inflammatory diseases should promote the development of novel and effective treatment strategies for intractable inflammatory diseases.
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