{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:07:41Z","timestamp":1789992461440,"version":"4.0.1"},"reference-count":41,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2018,7,3]],"date-time":"2018-07-03T00:00:00Z","timestamp":1530576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"},{"start":{"date-parts":[[2018,7,3]],"date-time":"2018-07-03T00:00:00Z","timestamp":1530576000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"},{"start":{"date-parts":[[2018,7,3]],"date-time":"2018-07-03T00:00:00Z","timestamp":1530576000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100008460","name":"National Center for Complementary and Integrative Health","doi-asserted-by":"publisher","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100008460","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["Intramural Research Program - DDIR Innovation Award"],"award-info":[{"award-number":["Intramural Research Program - DDIR Innovation Award"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Child Heath and Human Development","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Neuropathic pain resulting from nerve injury can become persistent and difficult to treat but the molecular signaling responsible for its development remains poorly described. Here, we identify the neuronal stress sensor dual leucine zipper kinase (DLK; Map3k12) as a key molecule controlling the maladaptive pathways that lead to pain following injury. Genetic or pharmacological inhibition of DLK reduces mechanical hypersensitivity in a mouse model of neuropathic pain. Furthermore, DLK inhibition also prevents the spinal cord microgliosis that results from nerve injury and arises distant from the injury site. These striking phenotypes result from the control by DLK of a transcriptional program in somatosensory neurons regulating the expression of numerous genes implicated in pain pathogenesis, including the immune gene Csf1. Thus, activation of DLK is an early event, or even the master regulator, controlling a wide variety of pathways downstream of nerve injury that ultimately lead to chronic pain.<\/jats:p>","DOI":"10.7554\/elife.33910","type":"journal-article","created":{"date-parts":[[2018,7,2]],"date-time":"2018-07-02T20:25:15Z","timestamp":1530563115000},"source":"Crossref","is-referenced-by-count":60,"title":["Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury"],"prefix":"10.7554","volume":"7","author":[{"given":"Josette J","family":"Wlaschin","sequence":"first","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob M","family":"Gluski","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen","family":"Nguyen","sequence":"additional","affiliation":[{"name":"National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Silberberg","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James H","family":"Thompson","sequence":"additional","affiliation":[{"name":"National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3131-0728","authenticated-orcid":true,"given":"Alexander T","family":"Chesler","sequence":"additional","affiliation":[{"name":"National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9274-3615","authenticated-orcid":true,"given":"Claire E","family":"Le Pichon","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2018,7,3]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.cell.2009.09.028","article-title":"Cellular and molecular mechanisms of pain","volume":"139","author":"Basbaum","year":"2009","journal-title":"Cell"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1038\/nn.3155","article-title":"P2X4R+ microglia drive neuropathic pain","volume":"15","author":"Beggs","year":"2012","journal-title":"Nature Neuroscience"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"14e1","DOI":"10.1016\/j.pain.2005.10.036","article-title":"Assessment and analysis of mechanical allodynia-like behavior induced by spared nerve injury (SNI) in the mouse","volume":"122","author":"Bourquin","year":"2006","journal-title":"Pain"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.pain.2010.05.005","article-title":"Differential ATF3 expression in dorsal root ganglion neurons reveals the profile of primary afferents engaged by diverse noxious chemical stimuli","volume":"150","author":"Br\u00e1z","year":"2010","journal-title":"Pain"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1083\/jcb.200410136","article-title":"Sunday Driver links axonal transport to damage signaling","volume":"168","author":"Cavalli","year":"2005","journal-title":"The Journal of Cell Biology"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1038\/nn.4549","article-title":"Identification of spinal circuits involved in touch-evoked dynamic mechanical pain","volume":"20","author":"Cheng","year":"2017","journal-title":"Nature Neuroscience"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"121","DOI":"10.3389\/fncel.2014.00121","article-title":"Fractalkine\/CX3CR1 signaling during neuropathic pain","volume":"8","author":"Clark","year":"2014","journal-title":"Frontiers in Cellular Neuroscience"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0304-3959(00)00276-1","article-title":"Spared nerve injury: an animal model of persistent peripheral neuropathic pain","volume":"87","author":"Decosterd","year":"2000","journal-title":"Pain"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"24788","DOI":"10.1074\/jbc.271.40.24788","article-title":"Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2","volume":"271","author":"Fan","year":"1996","journal-title":"The Journal of Biological Chemistry"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.nbd.2014.05.015","article-title":"DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury","volume":"69","author":"Fernandes","year":"2014","journal-title":"Neurobiology of Disease"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.exer.2013.04.021","article-title":"JUN regulates early transcriptional responses to axonal injury in retinal ganglion cells","volume":"112","author":"Fernandes","year":"2013","journal-title":"Experimental Eye Research"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1083\/jcb.201103153","article-title":"DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity","volume":"194","author":"Ghosh","year":"2011","journal-title":"The Journal of Cell Biology"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nri3621","article-title":"Pathological pain and the neuroimmune interface","volume":"14","author":"Grace","year":"2014","journal-title":"Nature Reviews Immunology"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/nn.4189","article-title":"Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain","volume":"19","author":"Guan","year":"2016","journal-title":"Nature Neuroscience"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1126\/science.1165527","article-title":"Axon regeneration requires a conserved MAP kinase pathway","volume":"323","author":"Hammarlund","year":"2009","journal-title":"Science"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"10729","DOI":"10.1523\/JNEUROSCI.0539-14.2014","article-title":"ZPK\/DLK and MKK4 form the critical gateway to axotomy-induced motoneuron death in neonates","volume":"34","author":"Itoh","year":"2014","journal-title":"Journal of Neuroscience"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.1016\/j.pain.2013.06.022","article-title":"Glia and pain: is chronic pain a gliopathy?","volume":"154","author":"Ji","year":"2013","journal-title":"Pain"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"re14","DOI":"10.1126\/stke.2522004re14","article-title":"Cell signaling and the genesis of neuropathic pain","volume":"2004","author":"Ji","year":"2004","journal-title":"Science Signaling"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/0006-8993(92)90315-Z","article-title":"Co-localized but target-unrelated expression of vasoactive intestinal polypeptide and galanin in rat dorsal root ganglion neurons after peripheral nerve crush injury","volume":"582","author":"Kashiba","year":"1992","journal-title":"Brain Research"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"e20725","DOI":"10.7554\/eLife.20725","article-title":"Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult","volume":"6","author":"Larhammar","year":"2017","journal-title":"eLife"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1016\/j.neuron.2015.05.033","article-title":"Reduction of neuropathic and inflammatory pain through inhibition of the tetrahydrobiopterin pathway","volume":"86","author":"Latremoliere","year":"2015","journal-title":"Neuron"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"eaag0394","DOI":"10.1126\/scitranslmed.aag0394","article-title":"Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease","volume":"9","author":"Le Pichon","year":"2017","journal-title":"Science Translational Medicine"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1016\/S0306-4522(98)00068-2","article-title":"Partial and complete sciatic nerve injuries induce similar increases of neuropeptide Y and vasoactive intestinal peptide immunoreactivities in primary sensory neurons and their central projections","volume":"86","author":"Ma","year":"1998","journal-title":"Neuroscience"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/nn.2290","article-title":"A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration","volume":"12","author":"Miller","year":"2009","journal-title":"Nature Neuroscience"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1021\/jm5013984","article-title":"Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models","volume":"58","author":"Patel","year":"2015","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"2553","DOI":"10.1084\/jem.20122832","article-title":"Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration","volume":"210","author":"Pozniak","year":"2013","journal-title":"The Journal of Experimental Medicine"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1126\/science.aag2590","article-title":"How neuroinflammation contributes to neurodegeneration","volume":"353","author":"Ransohoff","year":"2016","journal-title":"Science"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/j.cell.2014.10.010","article-title":"iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging","volume":"159","author":"Renier","year":"2014","journal-title":"Cell"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1038\/nm.4397","article-title":"Microglia emerge as central players in brain disease","volume":"23","author":"Salter","year":"2017","journal-title":"Nature Medicine"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1016\/j.cell.2016.01.032","article-title":"Axon degeneration gated by retrograde activation of somatic pro-apoptotic signaling","volume":"164","author":"Simon","year":"2016","journal-title":"Cell"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/0361-9230(93)90284-I","article-title":"The response of central glia to peripheral nerve injury","volume":"30","author":"Svensson","year":"1993","journal-title":"Brain Research Bulletin"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1038\/nm.3852","article-title":"The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase","volume":"21","author":"Vicu\u00f1a","year":"2015","journal-title":"Nature Medicine"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/j.neuron.2012.02.008","article-title":"Deconstructing the neuropathic pain phenotype to reveal neural mechanisms","volume":"73","author":"von Hehn","year":"2012","journal-title":"Neuron"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1016\/j.celrep.2018.03.071","article-title":"Sarm1\/Myd88-5 regulates neuronal intrinsic immune response to traumatic axonal injuries","volume":"23","author":"Wang","year":"2018","journal-title":"Cell Reports"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"4039","DOI":"10.1073\/pnas.1211074110","article-title":"DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury","volume":"110","author":"Watkins","year":"2013","journal-title":"PNAS"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"4045","DOI":"10.1073\/pnas.1211284110","article-title":"Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death","volume":"110","author":"Welsbie","year":"2013","journal-title":"PNAS"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1016\/j.emc.2015.11.002","article-title":"Emergency medicine clinics of north america","volume":"34","author":"Wilkerson","year":"2016","journal-title":"Emerg Med Clin N Am"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1523\/JNEUROSCI.3586-11.2012","article-title":"A conditioning lesion protects axons from degeneration via the Wallenda\/DLK MAP kinase signaling cascade","volume":"32","author":"Xiong","year":"2012","journal-title":"Journal of Neuroscience"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1083\/jcb.201006039","article-title":"Protein turnover of the Wallenda\/DLK kinase regulates a retrograde response to axonal injury","volume":"191","author":"Xiong","year":"2010","journal-title":"The Journal of Cell Biology"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/j.cell.2009.06.023","article-title":"The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration","volume":"138","author":"Yan","year":"2009","journal-title":"Cell"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"3551","DOI":"10.1523\/JNEUROSCI.5290-05.2006","article-title":"A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance","volume":"26","author":"Zhuang","year":"2006","journal-title":"Journal of Neuroscience"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/33910\/elife-33910-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/33910\/elife-33910-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/33910","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:51:56Z","timestamp":1697057516000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/33910"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,3]]},"references-count":41,"alternative-id":["10.7554\/eLife.33910"],"URL":"https:\/\/doi.org\/10.7554\/elife.33910","archive":["CLOCKSS"],"relation":{"references":[{"id-type":"uri","id":"https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSM1626431","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.33910.036","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.33910.037","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,3]]},"article-number":"e33910"}}