{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:18:27Z","timestamp":1793254707711,"version":"4.5.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T00:00:00Z","timestamp":1657756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971054, 81771197, 81874171"],"award-info":[{"award-number":["81971054, 81771197, 81874171"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Histone lysine crotonylation (KCR), a novel epigenetic modification, is important in regulating a broad spectrum of biological processes and various diseases. However, whether KCR is involved in neuropathic pain remains to be elucidated. We found KCR occurs in macrophages, sensory neurons, and satellite glial cells of trigeminal ganglia (TG), neurons, astrocytes, and microglia of the medulla oblongata. KCR in TG was detected mainly in small and medium sensory neurons, to a lesser extent in large neurons. Peripheral nerve injury elevated KCR levels in macrophages in the trigeminal and dorsal root ganglia and microglia in the medulla oblongata but reduced KCR levels in sensory neurons. Inhibition of histone crotonyltransferases (p300) by intra-TG or intrathecal administration of C646 significantly alleviated partial infraorbital nerve transection (pIONT)- or spinal nerve ligation (SNL)-induced mechanical allodynia and thermal hyperalgesia. Intra-TG or intrathecal administration of Crotonyl coenzyme A trilithium salt to upregulate KCR dose-dependently induced mechanical allodynia and thermal hyperalgesia in mice. Mechanismly, inhibition of p300 alleviated pIONT-induced macrophage activation and reduced the expression of pain-related inflammatory cytokines\n                    <jats:italic>Tnf\u03b1<\/jats:italic>\n                    ,\n                    <jats:italic>Il1\u03b2<\/jats:italic>\n                    and chemokines\n                    <jats:italic>Ccl2<\/jats:italic>\n                    and\n                    <jats:italic>Cxcl10<\/jats:italic>\n                    . Correspondingly, exogenous crotonyl-CoA induced macrophage activation and the expression of\n                    <jats:italic>Tnf\u03b1<\/jats:italic>\n                    ,\n                    <jats:italic>Il1\u03b2<\/jats:italic>\n                    ,\n                    <jats:italic>Il6<\/jats:italic>\n                    ,\n                    <jats:italic>Ccl2<\/jats:italic>\n                    and\n                    <jats:italic>Ccl7<\/jats:italic>\n                    in TG, which C646 can repress. These findings suggest that\n                    <jats:italic>histone crotonylation<\/jats:italic>\n                    might be functionally involved in neuropathic pain and neuroinflammation regulation.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.885685","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T02:50:47Z","timestamp":1657767047000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":42,"title":["Involvement of Histone Lysine Crotonylation in the Regulation of Nerve-Injury-Induced Neuropathic Pain"],"prefix":"10.3389","volume":"13","author":[{"given":"Yu","family":"Zou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue-Hui","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-Chi","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei-Fei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Yu","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Fei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu-Lu","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue-Juan","family":"Ling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bao-Chun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1152\/physrev.00045.2019","article-title":"Neuropathic Pain: From Mechanisms to Treatment","volume":"101","author":"Finnerup","year":"2021","journal-title":"Physiol Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-061620-044044","article-title":"Structural Insights Accelerate the Discovery of Opioid Alternatives","volume":"90","author":"Che","year":"2021","journal-title":"Annu Rev Biochem"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20210920","article-title":"Znf382 Controls Mouse Neuropathic Pain Via Silencer-Based Epigenetic Inhibition of Cxcl13 in Drg Neurons","volume":"218","author":"Ma","year":"2021","journal-title":"J Exp Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3438","article-title":"A Long Noncoding Rna Contributes to Neuropathic Pain by Silencing Kcna2 in Primary Afferent Neurons","volume":"16","author":"Zhao","year":"2013","journal-title":"Nat Neurosci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2217\/epi.14.75","article-title":"Epigenetic Regulation of Chronic Pain","volume":"7","author":"Liang","year":"2015","journal-title":"Epigenomics"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.01.012","article-title":"Chronic Pain: Emerging Evidence for the Involvement of Epigenetics","volume":"73","author":"Denk","year":"2012","journal-title":"Neuron"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.08.008","article-title":"Identification of 67 Histone Marks and Histone Lysine Crotonylation as a New Type of Histone Modification","volume":"146","author":"Tan","year":"2011","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.624914","article-title":"The Regulation and Function of Histone Crotonylation","volume":"9","author":"Ntorla","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.02.029","article-title":"Intracellular Crotonyl-Coa Stimulates Transcription Through P300-Catalyzed Histone Crotonylation","volume":"58","author":"Sabari","year":"2015","journal-title":"Mol Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/cr.2017.68","article-title":"Class I Histone Deacetylases Are Major Histone Decrotonylases: Evidence for Critical and Broad Function of Histone Crotonylation in Transcription","volume":"27","author":"Wei","year":"2017","journal-title":"Cell Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1186\/s13072-021-00385-9","article-title":"Histone Crotonylation-Centric Gene Regulation","volume":"14","author":"Li","year":"2021","journal-title":"Epigenet Chromatin"},{"key":"B12","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1016\/j.molcel.2019.09.029","article-title":"Recognition of Histone Crotonylation by Taf14 Links Metabolic State to Gene Expression","volume":"76","author":"Gowans","year":"2019","journal-title":"Mol Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.molcel.2017.07.011","article-title":"Chromodomain Protein Cdyl Acts as a Crotonyl-Coa Hydratase to Regulate Histone Crotonylation and Spermatogenesis","volume":"67","author":"Liu","year":"2017","journal-title":"Mol Cell"},{"key":"B14","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.stem.2020.12.009","article-title":"Histone Crotonylation Promotes Mesoendodermal Commitment of Human Embryonic Stem Cells","volume":"28","author":"Fang","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.024455","article-title":"Histone Lysine Crotonylation During Acute Kidney Injury in Mice","volume":"9","author":"Ruiz-Andres","year":"2016","journal-title":"Dis Model Mech"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI98071","article-title":"Hiv Latency Is Reversed by Acss2-Driven Histone Crotonylation","volume":"128","author":"Jiang","year":"2018","journal-title":"J Clin Invest"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjz019","article-title":"Hdac-Dependent Decrease in Histone Crotonylation During DNA Damage","volume":"11","author":"Abu-Zhayia","year":"2019","journal-title":"J Mol Cell Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2018.11.025","article-title":"Chromodomain Y-Like Protein-Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors","volume":"85","author":"Liu","year":"2019","journal-title":"Biol Psychiatry"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000002156","article-title":"G Protein-Coupled Receptor Gpr151 Is Involved in Trigeminal Neuropathic Pain Through the Induction of Gbetagamma\/Extracellular Signal-Regulated Kinase-Mediated Neuroinflammation in the Trigeminal Ganglion","volume":"162","author":"Jiang","year":"2021","journal-title":"Pain"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81950","article-title":"Cxcl13 Drives Spinal Astrocyte Activation and Neuropathic Pain Via Cxcr5","volume":"126","author":"Jiang","year":"2016","journal-title":"J Clin Invest"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/srep34836","article-title":"Cxcl13\/Cxcr5 Enhances Sodium Channel Nav1.8 Current Density Via P38 Map Kinase in Primary Sensory Neurons Following Inflammatory Pain","volume":"6","author":"Wu","year":"2016","journal-title":"Sci Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.20.040180.002301","article-title":"Efficient Analysis of Experimental Observations","volume":"20","author":"Dixon","year":"1980","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/0304-3959(88)90026-7","article-title":"A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia","volume":"32","author":"Hargreaves","year":"1988","journal-title":"Pain"},{"key":"B24","doi-asserted-by":"publisher","first-page":"891","DOI":"10.12688\/f1000research.18338.2","article-title":"A Refinement to the Formalin Test in Mice","volume":"8","author":"Lopes","year":"2019","journal-title":"F1000Res"},{"key":"B25","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1146\/annurev.ne.06.030183.002121","article-title":"Spinal and Trigeminal Mechanisms of Nociception","volume":"6","author":"Dubner","year":"1983","journal-title":"Annu Rev Neurosci"},{"key":"B26","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1038\/s41467-019-13839-2","article-title":"Dorsal Root Ganglion Macrophages Contribute to Both the Initiation and Persistence of Neuropathic Pain","volume":"11","author":"Yu","year":"2020","journal-title":"Nat Commun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2020.107581","article-title":"Chemokines in Chronic Pain: Cellular and Molecular Mechanisms and Therapeutic Potential","volume":"212","author":"Jiang","year":"2020","journal-title":"Pharmacol Ther"},{"key":"B28","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.celrep.2013.08.051","article-title":"The Organization of Submodality-Specific Touch Afferent Inputs in the Vibrissa Column","volume":"5","author":"Sakurai","year":"2013","journal-title":"Cell Rep"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf8924","article-title":"Pain Regulation by Non-Neuronal Cells and Inflammation","volume":"354","author":"Ji","year":"2016","journal-title":"Science"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.03.028","article-title":"Molecular Coupling of Histone Crotonylation and Active Transcription by Af9 Yeats Domain","volume":"62","author":"Li","year":"2016","journal-title":"Mol Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.molcel.2014.03.027","article-title":"Nonenzymatic Protein Acylation as a Carbon Stress Regulated by Sirtuin Deacylases","volume":"54","author":"Wagner","year":"2014","journal-title":"Mol Cell"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI86812","article-title":"Local Gabaergic Signaling Within Sensory Ganglia Controls Peripheral Nociceptive Transmission","volume":"127","author":"Du","year":"2017","journal-title":"J Clin Invest"},{"key":"B33","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/s41419-021-03987-z","article-title":"Protein Lysine Crotonylation: Past, Present, Perspective","volume":"12","author":"Jiang","year":"2021","journal-title":"Cell Death Dis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.885685\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T02:50:57Z","timestamp":1657767057000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.885685\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,14]]},"references-count":33,"alternative-id":["10.3389\/fimmu.2022.885685"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.885685","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,14]]},"article-number":"885685"}}