{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T15:04:47Z","timestamp":1774278287946,"version":"3.50.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Spinal cord injury (SCI)-induced neuropathic pain affects up to 60% of individuals with SCI and is closely linked to microglia-driven neuroinflammation. Neuroinflammatory processes after SCI are major contributors to the development and persistence of chronic pain. MicroRNAs (miRNAs) have emerged as regulators of neuroinflammation. There are higher levels of circulating miR-19a and miR-19b in persons living with SCI with neuropathic pain compared to those with no pain. These miRNAs are associated with altered the neuroprotective genes Nurr1 and Nur77.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Primary microglia cultures and a rat spinal cord injury model were used to investigate the regulatory effects of miR-19a and miR-19b on Nurr1 and Nur77 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our study shows that miR-19a and miR-19b and their binding sites in Nurr1\u2019s 3\u2032 UTR are highly conserved across vertebrates, suggesting functional importance. Through\n                      <jats:italic>in vitro<\/jats:italic>\n                      microglia cultures and\n                      <jats:italic>in vivo<\/jats:italic>\n                      rat SCI models, we demonstrate that these miRNAs negatively regulate Nurr1, Nur77, and inflammatory gene expression. Protein\u2013protein interaction network analysis highlights transcription factors such as MYC, RUNX1, and STAT3 as central to this regulatory network.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings support a model in which miR-19a and miR-19b contribute to microglia-driven neuroinflammation after SCI and highlight their potential as therapeutic targets to reduce neuropathic pain.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fncel.2026.1783899","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:16:51Z","timestamp":1774275411000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["miR-19a-3p and miR-19b-3p repress Nurr1 and Nur77 to promote microglial inflammation after spinal cord injury"],"prefix":"10.3389","volume":"20","author":[{"given":"Faezeh","family":"Sahebdel","sequence":"first","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Miller School of Medicine, University of Miami","place":["Miami, FL, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aliabbas","family":"Zia","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire Sainte-Justine","place":["Montreal, QC, Canada"]},{"name":"Department of Pharmacology, Universit\u00e9 de Montr\u00e9al","place":["Montreal, QC, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hector Ramiro","family":"Quint\u00e1","sequence":"additional","affiliation":[{"name":"National Scientific and Technical Research Council (CONICET)","place":["Buenos Aires, Argentina"]},{"name":"Laboratorio de Medicina Experimental, \u201cDr. Toblli\u201d \u2013 Hospital Aleman","place":["Buenos Aires, Argentina"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andres","family":"Stucky","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Miller School of Medicine, University of Miami","place":["Miami, FL, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leslie R.","family":"Morse","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, Miller School of Medicine, University of Miami","place":["Miami, FL, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie K.","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Diagnostics and Biological Sciences, School of Dentistry, University of Minnesota","place":["Minneapolis, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo A.","family":"Battaglino","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Miller School of Medicine, University of Miami","place":["Miami, FL, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/j.1460-9568.2010.07500.x","article-title":"Autophagy, inflammation and neurodegenerative disease","volume":"33","author":"Alirezaei","year":"2011","journal-title":"Eur. J. Neurosci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"11299","DOI":"10.1073\/pnas.1902490116","article-title":"NURR1 activation in skeletal muscle controls systemic energy homeostasis","volume":"116","author":"Amoasii","year":"2019","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"11351","DOI":"10.1074\/jbc.M111.272427","article-title":"Nurr1 protein is required for N-methyl-D-aspartic acid (NMDA) receptor-mediated neuronal survival","volume":"287","author":"Barneda-Zahonero","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","article-title":"MicroRNAs: genomics, biogenesis, mechanism, and function","volume":"116","author":"Bartel","year":"2004","journal-title":"Cell"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.cell.2009.03.024","article-title":"A Nurr1 pathway for neuroprotection","volume":"137","author":"Bensinger","year":"2009","journal-title":"Cell"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1038\/ng1590","article-title":"Identification of hundreds of conserved and nonconserved human microRNAs","volume":"37","author":"Bentwich","year":"2005","journal-title":"Nat. Genet."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.neulet.2017.07.022","article-title":"Proteomic analysis of the effects of Nur77 on lipopolysaccharide-induced microglial activation","volume":"659","author":"Chen","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"325","DOI":"10.3389\/fncel.2018.00325","article-title":"The role of KLF4 in Alzheimer\u2019s disease","volume":"12","author":"Cheng","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"88","DOI":"10.3390\/genes8030088","article-title":"MYC in regulating immunity: metabolism and beyond","volume":"8","author":"Gnanaprakasam","year":"2017","journal-title":"Genes."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"125","DOI":"10.3389\/fnmol.2019.00125","article-title":"MicroRNAs in microglia: how do microRNAs affect activation, inflammation, polarization of microglia and mediate the interaction between microglia and glioma?","volume":"12","author":"Guo","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/s40122-015-0033-y","article-title":"Management of neuropathic pain associated with spinal cord injury","volume":"4","author":"Hagen","year":"2015","journal-title":"Pain Ther."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/glia.10161","article-title":"Microglia as a source and target of cytokines","volume":"40","author":"Hanisch","year":"2002","journal-title":"Glia"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1002\/glia.24012","article-title":"The thrombin receptor modulates astroglia-neuron trophic coupling and neural repair after spinal cord injury","volume":"69","author":"Kim","year":"2021","journal-title":"Glia"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"2543","DOI":"10.1016\/j.bbamcr.2014.06.010","article-title":"NR4A nuclear receptors are orphans but not lonesome","volume":"1843","author":"Kurakula","year":"2014","journal-title":"Biochim. Biophys. Acta, Mol. Cell Res."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1097\/WNR.0000000000000665","article-title":"Nurr1 expression is modified by inflammation in microglia","volume":"27","author":"Lallier","year":"2016","journal-title":"Neuroreport"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/ng1066","article-title":"Mutations in NR4A2 associated with familial Parkinson disease","volume":"33","author":"Le","year":"2003","journal-title":"Nat. Genet."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s12974-025-03362-1","article-title":"Microglial C\/EBP\u03b2-Fcgr1 regulatory axis blocking inhibits microglial pyroptosis and improves neurological recovery","volume":"22","author":"Li","year":"2025","journal-title":"J. Neuroinflammation"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"9248","DOI":"10.1523\/JNEUROSCI.1731-12.2012","article-title":"Conditional expression of Parkinson's disease-related mutant \u03b1-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1","volume":"32","author":"Lin","year":"2012","journal-title":"J. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1111\/jnc.13907","article-title":"Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation-induced cell death","volume":"140","author":"Liu","year":"2017","journal-title":"J. Neurochem."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"3865","DOI":"10.1093\/nar\/gkw116","article-title":"Distribution of miRNA expression across human tissues","volume":"44","author":"Ludwig","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s00540-018-2579-4","article-title":"Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain","volume":"33","author":"Matsuda","year":"2019","journal-title":"J. Anesth."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"3916","DOI":"10.4049\/jimmunol.173.6.3916","article-title":"Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs","volume":"173","author":"Olson","year":"2004","journal-title":"J. Immunol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/S0165-0270(03)00145-6","article-title":"Efficient technique for immortalization of murine microglial cells relevant for studies in murine models of multiple sclerosis","volume":"128","author":"Olson","year":"2003","journal-title":"J. Neurosci. Methods"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.brainres.2008.05.022","article-title":"Nurr1 deficiency predisposes to lactacystin-induced dopaminergic neuron injury in vitro and in vivo","volume":"1222","author":"Pan","year":"2008","journal-title":"Brain Res."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"107","DOI":"10.3892\/mmr.2019.10828","article-title":"Altered Nurr1 protein expression in the hippocampal CA1 region following transient global cerebral ischemia","volume":"21","author":"Park","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e0188177","DOI":"10.1371\/journal.pone.0188177","article-title":"Long 3'UTR of Nurr1 mRNAs is targeted by miRNAs in mesencephalic dopamine neurons","volume":"12","author":"Pereira","year":"2017","journal-title":"PLoS One"},{"key":"ref877","doi-asserted-by":"publisher","first-page":"2084","DOI":"10.1089\/neu.2020.7571","article-title":"Intraspinal administration of netrin-1 promotes locomotor recovery after complete spinal cord transection","volume":"38","author":"Quint\u00e1","year":"2021","journal-title":"J. Neurotrauma"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.1177\/08977151251387696","article-title":"Netrin-1 Therapy Restores Partial Hindlimb Movement in a Rat Model of High-Severity Chronic Spinal Cord Injury","author":"Schmidt","year":"2025","journal-title":"J. Neurotrauma"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"2239","DOI":"10.3390\/cancers15082239","article-title":"STAT3 inhibition attenuates MYC expression by modulating co-activator recruitment and suppresses medulloblastoma tumor growth by augmenting cisplatin efficacy in vivo","volume":"15","author":"Rohrer","year":"2023","journal-title":"Cancer"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"10601","DOI":"10.3390\/ijms251910601","article-title":"Transcriptomic profiling of primary microglia: effects of miR-19a-3p and miR-19b-3p on microglia activation","volume":"25","author":"Sahebdel","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.omto.2021.01.005","article-title":"miR-19a\/b promote EMT and proliferation in glioma cells via SEPT7-AKT-NF-\u03baB pathway","volume":"20","author":"Wang","year":"2021","journal-title":"Molecular Therapy Oncolytics."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.tibs.2014.02.003","article-title":"FOXO transcription factors: key regulators of cellular quality control","volume":"39","author":"Webb","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3171\/2012.4.aospine1245","article-title":"Clinical predictors of neurological outcome, functional status, and survival after traumatic spinal cord injury: a systematic review","volume":"17","author":"Wilson","year":"2012","journal-title":"J. Neurosurg. Spine"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"2446","DOI":"10.4161\/cc.29420","article-title":"Isolated spinal cord contusion in rats induces chronic brain neuroinflammation, neurodegeneration, and cognitive impairment: involvement of cell cycle activation","volume":"13","author":"Wu","year":"2014","journal-title":"Cell Cycle"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"10989","DOI":"10.1523\/JNEUROSCI.5110-13.2014","article-title":"Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways","volume":"34","author":"Wu","year":"2014","journal-title":"J. Neurosci."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1089\/neur.2021.0011","article-title":"Hsa-MiR-19a-3p and hsa-MiR-19b-3p are associated with spinal cord injury-induced neuropathic pain: findings from a genome-wide MicroRNA expression profiling screen","volume":"2","author":"Ye","year":"2021","journal-title":"Neurotrauma reports."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1158\/2767-9764.CRC-21-0073","article-title":"Nuclear receptor 4A2 (NR4A2\/NURR1) regulates autophagy and chemoresistance in pancreatic ductal adenocarcinoma","volume":"1","author":"Zarei","year":"2021","journal-title":"Cancer Research Commun."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1126\/science.276.5310.248","article-title":"Dopamine neuron agenesis in Nurr1-deficient mice","volume":"276","author":"Zetterstrom","year":"1997","journal-title":"Science"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.cmet.2011.01.009","article-title":"AMPK-dependent phosphorylation of ULK1 induces autophagy","volume":"13","author":"Zhao","year":"2011","journal-title":"Cell Metab."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.gendis.2015.12.002","article-title":"Mitochondrial dysfunction activates the AMPK signaling and autophagy to promote cell survival","volume":"3","author":"Zhao","year":"2016","journal-title":"Genes & diseases."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.tibs.2007.02.006","article-title":"A developmental view of microRNA function","volume":"32","author":"Zhao","year":"2007","journal-title":"Trends Biochem. Sci."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"736","DOI":"10.2174\/1874467214666210917141541","article-title":"Key miRNAs in modulating aging and longevity: a focus on signaling pathways and cellular targets","volume":"15","author":"Zia","year":"2022","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.ijbiomac.2021.08.013","article-title":"A review study on the modulation of SIRT1 expression by miRNAs in aging and age-associated diseases","volume":"188","author":"Zia","year":"2021","journal-title":"Int. J. Biol. Macromol."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2026.1783899\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:16:51Z","timestamp":1774275411000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2026.1783899\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":43,"alternative-id":["10.3389\/fncel.2026.1783899"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2026.1783899","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,23]]},"article-number":"1783899"}}