Abstract
Recent evidence suggests that transient receptor potential melastatin 2 (TRPM2) expressed in immune cells plays an important role in immune and inflammatory responses. We recently reported that TRPM2 expressed in macrophages and spinal microglia contributes to the pathogenesis of inflammatory and neuropathic pain aggravating peripheral and central pronociceptive inflammatory responses in mice. To further elucidate the contribution of TRPM2 expressed by peripheral immune cells to neuropathic pain, we examined the development of peripheral nerve injury-induced neuropathic pain and the infiltration of immune cells (particularly macrophages) into the injured nerve and spinal cord by using bone marrow (BM) chimeric mice by crossing wildtype (WT) and TRPM2-knockout (TRPM2-KO) mice. Four types of BM chimeric mice were prepared, in which irradiated WT or TRPM2-KO recipient mice were transplanted with either WT-or TRPM2-KO donor mouse-derived green fluorescence protein-positive (GFP+) BM cells (TRPM2BM+/Rec+, TRPM2BM–/Rec+, TRPM2BM+/Rec–, and TRPM2BM–/Rec– mice). Mechanical allodynia induced by partial sciatic nerve ligation observed in TRPM2BM+/Rec+ mice was attenuated in TRPM2BM–/Rec+, TRPM2BM+/Rec–, and TRPM2BM–/Rec– mice. The numbers of GFP+ BM-derived cells and Iba1/GFP double-positive macrophages in the injured sciatic nerve did not differ among chimeric mice 14 days after the nerve injury. In the spinal cord, the number of GFP+ BM-derived cells, particularly GFP/Iba1 double-positive macrophages, was significantly decreased in the three TRPM2-KO chimeric mouse groups compared with TRPM2BM+/Rec+ mice. However, the numbers of GFP–/Iba1+ resident microglia did not differ among chimeric mice. These results suggest that TRPM2 plays an important role in the infiltration of peripheral immune cells, particularly macrophages, into the spinal cord, rather than the infiltration of peripheral immune cells into the injured nerves and activation of spinal-resident microglia. The spinal infiltration of macrophages mediated by TRPM2 may contribute to the pathogenesis of neuropathic pain.
Highlights
Neuropathic pain is a pathological pain condition that often results from peripheral nerve injury
In TRPM2BM+/Rec– and TRPM2BM–/Rec– mice, partial sciatic nerve ligation (pSNL) surgery had no effect on the 50% withdrawal threshold in the ipsilateral paw, and no significant mechanical allodynia was observed during the observed period, compared with pre-surgery (Day 0)
Neither the infiltration of GFP+ peripheral immune cells into the sciatic nerve, nor the number of Iba1+/GFP– resident microglia in the spinal dorsal horn, were affected 14 days after pSNL surgery. These findings suggest that transient receptor potential melastatin 2 (TRPM2) expressed in peripheral immune cells and other cells such as spinal microglia plays an important role in the spinal infiltration of macrophages following peripheral nerve injury, which may contribute to neuropathic pain
Summary
Neuropathic pain is a pathological pain condition that often results from peripheral nerve injury. Several lines of evidence suggest that neuroinflammation mediated by the interaction between immune cells and neurons plays an important role in neuropathic pain [1,2]. Pronociceptive inflammatory mediators released from the activated immune cells can induce the sensitization of nociceptors and increase the excitability of nociceptive primary afferent neurons (peripheral sensitization). Glial cells such as microglia and astrocytes receive signals from the injured peripheral neurons and become activated, which cause the generation of synaptic facilitation and enhanced responsiveness of nociceptive dorsal horn neurons (central sensitization) [3]. There is increasing evidence that peripheral nerve injury induces the infiltration of peripheral immune cells into the spinal cord, which contributes to the pathogenesis of neuropathic pain [4,5,6,7,8], the details and mechanisms still remain unclear
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