Bloodspinal cord barrier (BSCB) constitutes a physical and biochemical barrier between the spinal cord and the peripheral circulation. Peripheral nerve injury triggers the leakage of the BSCB through spinal inflammatory responses, resulting the influx of inflammatory mediators and the infiltration of peripheral Title Loaded From File immune cells [35,36]. Because spinally-infiltrated macrophages were differentiated as fully functional microglia, activation of both spinallyinfiltrated macrophages and spinal-resident microglia contributes to the induction and persistence of neuropathic pain [6]. Taken together, these results suggest that inhibition of neuropathic pain observed in TRPM2-KO chimeric mice is due to the reduction of TRPM2-mediated spinal infiltration of macrophages, as well as activation 24195657 of spinal-resident microglia. When using BM chimericmice to study conditions of the central nervous system (CNS), some limitations should be considered. Whole-body irradiation has been reported to have direct consequences on the CNS, such as disruption of the blood-brain barrier [37]. Although we cannot ignore the effect of irradiation, an indisputable body of evidence suggests that disruption of BSCB and spinal infiltration of peripheral immune cells clearly occurs following peripheral nerve injury even in non-irradiated animals [5,7,8,35,38]. The mechanism underlying TRPM2-mediated spinal infiltration of macrophages is still unknown. As described above, TRPM2 plays no role in the chemotactic activity of macrophages. By contrast, TRPM2 deficiency attenuates peripheral nerve injuryinduced activation of resident microglia, which precedes the spinal infiltration of macrophages. Consequently, TRPM2 deficiency may conceivably attenuate the initial deterioration of the spinal microenvironment by activating spinal-resident microglia, resulting in protection against disruption of the BSCB. However, leakage of the BSCB is not affected by intrathecal injection of minocycline, a microglial Title Loaded From File inhibitor, suggesting that BSCB disruption is independent of the activation of spinal-resident microglia [35]. Further investigations will be needed to elucidate the mechanisms.ConclusionsIn summary, the present study revealed that TRPM2 expressed in peripheral immune cells and/or other cells plays a role in the spinal infiltration of macrophages, rather than infiltration of peripheral immune 23727046 cells into the injured nerves and activation of spinal-resident microglia by using a set of WT/TRPM2-KO BM chimeric mice. Furthermore, the spinal infiltration of macrophages mediated through TRPM2 is suggested to contribute to the induction and persistence of neuropathic pain. The present findings provide evidence for a role of TRPM2 in neuropathic pain, suggesting that TRPM2 might be a promising target for the treatment of neuropathic pain.Author ContributionsConceived and designed the experiments: TN KI KH. Performed the experiments: KI KH KS KA. Analyzed the data: KI KH TN. Contributed reagents/materials/analysis tools: HS YM. Wrote the paper: KI KH TN SK.
Endocrine signaling was first linked to longevity when it was shown that mutations of daf-2, a homologue of the mammalian insulin/insulin-like growth factor-1 (IGF-1) receptor [1], dramatically prolonged the lifespan of the nematode Caenorhabditis elegans [2]. Genetic analysis subsequently demonstrated that reduction-offunction mutations affecting various genes in the insulin/IGF-1/ phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway prolon.Bloodspinal cord barrier (BSCB) constitutes a physical and biochemical barrier between the spinal cord and the peripheral circulation. Peripheral nerve injury triggers the leakage of the BSCB through spinal inflammatory responses, resulting the influx of inflammatory mediators and the infiltration of peripheral immune cells [35,36]. Because spinally-infiltrated macrophages were differentiated as fully functional microglia, activation of both spinallyinfiltrated macrophages and spinal-resident microglia contributes to the induction and persistence of neuropathic pain [6]. Taken together, these results suggest that inhibition of neuropathic pain observed in TRPM2-KO chimeric mice is due to the reduction of TRPM2-mediated spinal infiltration of macrophages, as well as activation 24195657 of spinal-resident microglia. When using BM chimericmice to study conditions of the central nervous system (CNS), some limitations should be considered. Whole-body irradiation has been reported to have direct consequences on the CNS, such as disruption of the blood-brain barrier [37]. Although we cannot ignore the effect of irradiation, an indisputable body of evidence suggests that disruption of BSCB and spinal infiltration of peripheral immune cells clearly occurs following peripheral nerve injury even in non-irradiated animals [5,7,8,35,38]. The mechanism underlying TRPM2-mediated spinal infiltration of macrophages is still unknown. As described above, TRPM2 plays no role in the chemotactic activity of macrophages. By contrast, TRPM2 deficiency attenuates peripheral nerve injuryinduced activation of resident microglia, which precedes the spinal infiltration of macrophages. Consequently, TRPM2 deficiency may conceivably attenuate the initial deterioration of the spinal microenvironment by activating spinal-resident microglia, resulting in protection against disruption of the BSCB. However, leakage of the BSCB is not affected by intrathecal injection of minocycline, a microglial inhibitor, suggesting that BSCB disruption is independent of the activation of spinal-resident microglia [35]. Further investigations will be needed to elucidate the mechanisms.ConclusionsIn summary, the present study revealed that TRPM2 expressed in peripheral immune cells and/or other cells plays a role in the spinal infiltration of macrophages, rather than infiltration of peripheral immune 23727046 cells into the injured nerves and activation of spinal-resident microglia by using a set of WT/TRPM2-KO BM chimeric mice. Furthermore, the spinal infiltration of macrophages mediated through TRPM2 is suggested to contribute to the induction and persistence of neuropathic pain. The present findings provide evidence for a role of TRPM2 in neuropathic pain, suggesting that TRPM2 might be a promising target for the treatment of neuropathic pain.Author ContributionsConceived and designed the experiments: TN KI KH. Performed the experiments: KI KH KS KA. Analyzed the data: KI KH TN. Contributed reagents/materials/analysis tools: HS YM. Wrote the paper: KI KH TN SK.
Endocrine signaling was first linked to longevity when it was shown that mutations of daf-2, a homologue of the mammalian insulin/insulin-like growth factor-1 (IGF-1) receptor [1], dramatically prolonged the lifespan of the nematode Caenorhabditis elegans [2]. Genetic analysis subsequently demonstrated that reduction-offunction mutations affecting various genes in the insulin/IGF-1/ phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway prolon.
