Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury

• Published in: eLife Vol. 7
• Main Authors: Wlaschin, Josette J, Gluski, Jacob M, Nguyen, Eileen, Silberberg, Hanna, Thompson, James H, Chesler, Alexander T, Le Pichon, Claire E
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 03-07-2018; eLife Sciences Publications, Ltd
• Subjects: Animals; Behavior; Chronic pain; Disease Models, Animal; Female; Gene expression; Gene Expression Regulation; Gliosis - enzymology; Gliosis - genetics; Gliosis - pathology; Gliosis - prevention & control; Hyperalgesia - enzymology; Hyperalgesia - genetics; Hyperalgesia - pathology; Hyperalgesia - prevention & control; Hypersensitivity; kinase; Kinases; Leucine zipper proteins; Macrophage Colony-Stimulating Factor - genetics; Macrophage Colony-Stimulating Factor - metabolism; Male; MAP Kinase Kinase Kinases - deficiency; MAP Kinase Kinase Kinases - genetics; mechanical allodynia; Mice; Mice, Transgenic; microglia; Microglia - enzymology; Microglia - pathology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuralgia; Neuralgia - enzymology; Neuralgia - genetics; Neuralgia - pathology; Neuralgia - prevention & control; Neurons; neuropathic; Neuroscience; Pain; Pain perception; Peripheral Nerve Injuries - enzymology; Peripheral Nerve Injuries - genetics; Peripheral Nerve Injuries - pathology; Phenotypes; Pipelines; Sciatic Nerve - enzymology; Sciatic Nerve - injuries; Sciatic Nerve - physiopathology; Sensory Receptor Cells - enzymology; Sensory Receptor Cells - pathology; Signal Transduction; somatosensation; Spinal cord; Spinal Cord - enzymology; Spinal Cord - pathology; Spinal cord injuries; Touch; Transcription; Transcription, Genetic; United States > US; neuropathic; mouse; kinase; pain; neuroscience; somatosensation; mechanical allodynia; microglia
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.33910

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;
) 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
. 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.