DLK mediates the neuronal intrinsic immune response and regulates glial reaction and neuropathic pain.

Inflammatory response triggered by nerve injury plays important roles in the development of neurological disorders, such as neuropathic pain. The signaling events leading to inflammation in the nervous system remain poorly understood. Here, by deleting Dlk in sensory neurons driven by Wnt1a-Cre, we show that dual leucine zipper kinase (DLK) is required for the neuronal intrinsic immune response to induce cytokines and chemokines such as Ccl2, Ccl7, and Ccl12 upon nerve injury. The DLK-controlled injury response in sensory neurons could regulate CD11b immune cell infiltration in the dorsal root ganglia, as well as microgliosis and astrogliosis in the spinal dorsal horn but not the ventral horn. Deficiency of Dlk drastically alleviates the neuropathic pain elicited by chronic constriction injury of the sciatic nerve. Thus, DLK is an essential component that mediates the neuronal intrinsic immune response to nerve injury in sensory neurons and regulates inflammation in the spinal cord.