TRPM2 Contributes to Inflammatory and Neuropathic Pain through the Aggravation of Pronociceptive Inflammatory Responses in Mice

Abstract

Accumulating evidence suggests that neuroimmune interactions contribute to pathological pain. Transient receptor potential melastatin 2 (TRPM2) is a nonselective Ca 2ϩ -permeable cation channel that acts as a sensor for reactive oxygen species. TRPM2 is expressed abundantly in immune cells and is important in inflammatory processes. The results of the present study show that TRPM2 plays a crucial role in inflammatory and neuropathic pain. While wild-type and TRPM2 knock-out mice showed no difference in their basal sensitivity to mechanical and thermal stimulation, nocifensive behaviors in the formalin test were reduced in TRPM2 knock-out mice. In carrageenan-induced inflammatory pain and sciatic nerve injury-induced neuropathic pain models, mechanical allodynia and thermal hyperalgesia were attenuated in TRPM2 knock-out mice. Carrageenan-induced inflammation and sciatic nerve injury increased the expression of TRPM2 mRNA in the inflamed paw and around the injured sciatic nerve, respectively. TRPM2 deficiency diminished the infiltration of neutrophils and the production of chemokine (C-X-C motif) ligand-2 (CXCL2), a major chemokine that recruits neutrophils, but did not alter the recruitment of F4/80-positive macrophages in the inflamed paw or around the injured sciatic nerve. Microglial activation after nerve injury was suppressed in the spinal cord of TRPM2 knock-out mice. Furthermore, CXCL2 production and inducible nitric oxide synthase induction were diminished in cultured macrophages and microglia derived from TRPM2 knock-out mice. Together, these results suggest that TRPM2 expressed in macrophages and microglia aggravates peripheral and spinal pronociceptive inflammatory responses and contributes to the pathogenesis of inflammatory and neuropathic pain.

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

“…Although not described in β-cells, a role for TRPM2 has been described in the inflammation through up-regulation of chemokines [42]. Inhibition of TRPM2 channels indeed prevents inflammation in a mouse model of colitis and inflammatory and neuropathic pain [42,43]. Thus TRPM2 channels could also contribute to MLDS-induced insulitis.…”

Physiological and Pathophysiological Roles of Transient Receptor Potential Channels in Microglia-Related CNS Inflammatory Diseases

“…29) TRPM2 is also involved in chemokine CXCL2 and NO production in cultured macrophages and microglia. 31,32) In line with these findings, TRPM2 regulates the migratory capacity of neutrophils and macrophages in response to ischemic brain injury, thereby secondarily perpetuating brain injury after the ischemic event. 43) Taken together, these results suggest that TRPM2 in microglia/macrophages could mainly contribute to the development of cerebral ischemic injury.…”

“…30) Using cultured microglia derived from wild-type and TRPM2 knockout mice, Haraguchi et al showed that TRPM2 is involved in NO production. 31) Subsequently, Miyake et al examined the intracellular signaling mechanisms underlying these phenomena and demonstrated that combined application of lipopolysaccharide (LPS) and interferon-γ can stimulate TRPM2-mediated extracellular Ca 2+ influx in cultured microglia. 32) They also showed that activation of TRPM2 results in proline-rich tyrosine kinase 2 (Pyk2)-mediated activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) signaling, leading to the increased NO production in microglia.…”

“…Microglial/Macrophagic TRPM2 Channels in Neuropathic Pain TRPM2 is thought to be involved in a range of pathological pain states, including neuropathic pain. 31,36,37) Evidence suggests that peripheral and spinal neuroinflammation mediated by the interaction between nociceptive neurons and immune/glial cells plays a pivotal role in neuropathic pain. 38) After peripheral nerve injury, pro-nociceptive inflammatory mediators, such as pro-inflammatory cytokines, chemokines, and excess ROS produced by peripheral tissues and the spinal cord, can lead to peripheral and central sensitization of nociceptive neurons.…”

“…TRPM2 is responsible for chemokine (C-X-C motif) ligand 2 (CXCL2) and NO production in macrophages and microglia, which aggravate peripheral and spinal pro-nociceptive inflammatory responses, respectively, in inflammatory and neuropathic pain models. 31,32) Furthermore, TRPM2 may play a role in the infiltration of peripheral immune cells into the spinal cord after peripheral nerve injury. 36) Consequently, TRPM2 is involved in a wide range of pathological pain states induced by peripheral and spinal neuroinflammation-such as inflammatory pain, osteoarthritic pain, neuropathic pain induced by peripheral nerve injury, chemotherapy-induced peripheral neuropathy, and painful diabetic neuropathy-rather than in physiological nociceptive pain.…”