Metabolites have recently been found to be involved in significant biological regulation and changes. Itaconate, an important intermediate metabolite isolated from the tricarboxylic acid cycle, is derived from cis-aconitate decarboxylation mediated by immune response gene 1 in mitochondrial matrix. Itaconate has emerged as a key autocrine regulatory component involved in the development and progression of inflammation and immunity. It could directly modify cysteine sites on functional substrate proteins which related to inflammasome, signal transduction, transcription, and cell death. Itaconate can be a connector among immunity, metabolism, and inflammation, which is of great significance for further understanding the mechanism of cellular immune metabolism. And it could be the potential choice for the treatment of inflammation and immune-related diseases. This study is a systematic review of the potential mechanisms of metabolite associated with different pathology conditions. We briefly summarize the structural characteristics and classical pathways of itaconate and its derivatives, with special emphasis on its promising role in future clinical application, in order to provide theoretical basis for future research and treatment intervention.

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Nerve injury–induced changes of gene expression in dorsal root ganglion (DRG) are critical for neuropathic pain genesis. However, how these changes occur remains elusive. Here we report the down-regulation of zinc finger protein 382 (ZNF382) in injured DRG neurons after nerve injury. Rescuing this down-regulation attenuates nociceptive hypersensitivity. Conversely, mimicking this down-regulation produces neuropathic pain symptoms, which are alleviated by C-X-C motif chemokine 13 (CXCL13) knockdown or its receptor CXCR5 knockout. Mechanistically, an identified cis-acting silencer at distal upstream of the Cxcl13 promoter suppresses Cxcl13 transcription via binding to ZNF382. Blocking this binding or genetically deleting this silencer abolishes the ZNF382 suppression on Cxcl13 transcription and impairs ZNF382-induced antinociception. Moreover, ZNF382 down-regulation disrupts the repressive epigenetic complex containing histone deacetylase 1 and SET domain bifurcated 1 at the silencer-promoter loop, resulting in Cxcl13 transcriptional activation. Thus, ZNF382 down-regulation is required for neuropathic pain likely through silencer-based epigenetic disinhibition of CXCL13, a key neuropathic pain player, in DRG neurons.

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The spinal cord (SC) is crucial for a myriad of somatosensory, autonomic signal processing, and transductions. Understanding the SC vascular structure and function thus plays an integral part in neuroscience and clinical research. However, the dense layers of myelinated ascending axons on the dorsal side inconveniently grant the SC tissue with high optical scattering property, which significantly hinders the imaging depth of the SC vasculature in vivo. Commonly used antiscattering techniques such as multiphoton fluorescence microscopy have low imaging speed and cannot capture the rapid vascular particle flow without significant motion blur. Here, advantage of the high penetration of near‐infrared (NIR)‐II fluorescence is taken to demonstrate a deep SC vascular structural image stack up to 350 µm, comparable to two‐photon microscopy. Furthermore, the red blood cells are labelled with the clinically approved NIR dye indocyanine. The combination of a fast NIR camera and indocyanine green‐red blood cells (RBCs) makes it possible to attain high‐speed 100 frame‐per‐second NIR‐II imaging to identify the corresponding changes in RBC velocity during the external hind leg stimulus. For the first time, it is established that the NIR‐II region would be a promising spectral window for SC imaging. NIR‐II fluorescence microscopy has excellent potential for clinical and basic science research on SC.

Nerve injury-induced gene expression change in the spinal cord is critical for neuropathic pain genesis. RNA N6-methyladenosine (m6A) modification represents an additional layer of gene regulation. We showed that spinal nerve ligation (SNL) upregulated the expression of matrix metallopeptidase 24 (MMP24) protein, but not Mmp24 mRNA, in the spinal cord neurons. Blocking the SNL-induced upregulation of spinal MMP24 attenuated local neuron sensitization, neuropathic pain development and maintenance. Conversely, mimicking MMP24 increase promoted the spinal ERK activation and produced evoked nociceptive hypersensitivity. Methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) and RNA Immunoprecipitation (RIP) assay indicated the decreased m6A enrichment in the Mmp24 mRNA under neuropathic pain condition. Moreover, fat-mass and obesity-associated protein (FTO) was colocalized with MMP24 in spinal neurons and shown increased binding to the Mmp24 mRNA in the spinal cord after SNL. Overexpression or suppression of FTO correlates with promotion or inhibition of MMP24 expression in cultured spinal cord neurons. In conclusion, SNL promoted the m6A eraser FTO binding to the Mmp24 mRNA, which subsequently facilitated the translation of MMP24 in the spinal cord, and ultimately contributed to neuropathic pain genesis.

Opioids are the last option for the pharmacological treatment of neuropathic pain, but their antinociceptive effects are limited. Decreased mu opioid receptor (MOR) expression in the peripheral nervous system may contribute to this. Here, we showed that nerve injury induced hypermethylation of the Oprm1 gene promoter and an increased expression of methyl-CpG binding protein 2 (MeCP2) in injured dorsal root ganglion (DRG). The downregulation of MOR in the DRG is closely related to the augmentation of MeCP2, an epigenetic repressor, which could recruit HDAC1 and bind to the methylated regions of the Oprm1 gene promoter. MeCP2 knockdown restored the expression of MOR in injured DRG and enhanced the analgesic effect of morphine, while the mimicking of this increase via the intrathecal infusion of viral vector-mediated MeCP2 was sufficient to reduce MOR in the DRG. Moreover, HDAC1 inhibition with suberoylanilide hydroxamic acid, an HDAC inhibitor, also prevented MOR reduction in the DRG of neuropathic pain mice, contributing to the augmentation of morphine analgesia effects. Mechanistically, upregulated MeCP2 promotes the binding of a high level of HDCA1 to hypermethylated regions of the Oprm1 gene promoter, reduces the acetylation of histone H3 (acH3) levels of the Oprm1 gene promoter, and attenuates Oprm1 transcription in injured DRG. Thus, upregulated MeCP2 and HDAC1 in Oprm1 gene promoter sites, negatively regulates MOR expression in injured DRG, mitigating the analgesic effect of the opioids. Targeting MeCP2/HDAC1 may thus provide a new solution for improving the therapeutic effect of opioids in a clinical setting.

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