Role of microglia in neuropathic pain

Abstract

Neuropathic pain is a debilitating pain state, which is often caused by peripheral nerve injury (PNI) arising from bone compression in cancer, diabetes, infection, autoimmune disease or physical injury. From general population studies, neuropathic pain affects up to 5% of the population. One of the hallmark symptoms of neuropathic pain is tactile allodynia (pain hypersensitivity to normal innocuous stimuli like light touching). Tactile allodynia is refractory to currently available treatments such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, and the mechanism of the neuropathic pain remains largely unknown. Recently, we found that activated spinal microglia of dorsal horn overexpressing P2X4 receptors after PNI which release brain-derived neurotrophic factor (BDNF). BDNF evokes a collapse of their transmembrane anion gradient in the secondary neurons of dorsal hone resulting in tactile allodynia (Nature, 2003 & 2005). More recently, we have reported that interferon-c plays an important role in activation of microglia and tactile allodynia. We have also found that CCL2, ligands for CCR2, increased P2X4R expression in microglial surface fraction. Moreover, chemokine CCL21 was rapidly expressed in small-sized DRG neurons after PNI and transported into the sensory nerve endings through the dorsal root. CCL21 deficient mice failed to overexpression of P2X4R in microglia and did not evoke tactile allodynia. Also, neutralizing antibodies for CCL21 inhibited tactile allodynia in wild type mice. The result indicates that CCL21 from damaged DRG neurons causes P2X4 overexpression in activated spinal microglia resulting in neuropathic pain. Various molecules in microglia are reported to play important roles in the relation to the neuropathic pain. However, how microglia regulate the expression of these molecules is poorly understood. Then, we examined to find a maestro controlling the expression of these molecules and found the transcription factor interferon-regulatory factor 8 (IRF8) as a critical regulator of the gene expression in microglia. IRF8 expression was upregulated only in microglia but not in neurons or astrocytes after PNI. IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states. IRF8 deficiency prevented these gene expressions in the spinal cord and neuropathic pain following PNI. These result indicate that IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype. In the talk, it will be additional about the finding of the role of IRF5.