A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain methods
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TRPV4 was required for pain-related behaviors following spared nerve injury.
Although sensory TRP channels are generally considered critical molecular sensors for mechanical, thermal, and chemical cues and contribute to both pain and itch sensations (, - ), the role of centrally expressed TRPV4 in neuropathic pain remains poorly understood. To test this possibility, we generated a well-established mouse model of SNI ( ) in both Trpv4 -/- (global Trpv4 KO) and congenic WT C57BL/6J mice. Strikingly, compared with WT mice, Trpv4 -/- mice had a significantly improved paw withdrawal threshold, a hallmark of mechanical allodynia, in both male and female mice following SNI ( ). To complement genetic ablation studies, we administered TRPV4 antagonist GSK219 once daily through repeated i.p. injections for 7 consecutive days starting on day 1 after SNI in WT mice and observed a marked increase in paw withdrawal threshold in a dose- and tim...
SNI upregulated TRPV4 expression in the spinal cord resident microglia.
Next, we investigated how SNI affects TRPV4 expression in the spinal cord. Compared with naive or sham mice, Trpv4 mRNA transcripts were substantially upregulated in the ipsilateral side of the spinal dorsal horn starting within 1 day and lasting for at least 14 days after SNI ( ). RNAscope assay further revealed the presence of Trpv4 mRNA transcripts in CX3CR1 + microglia in the spinal cord of Cx3cr1 CreER/+:tdTomato mice on day 7 after SNI ( ). Moreover, flow cytometric analysis using Trpv4 eGFP mice with CD11b + CD45 + gating strategy revealed that,compared with the contralateral side, the number of TRPV4-eGFP + CX3CR1 + - but not TRPV4-eGFP + CCR2 + - cells was markedly increased in the ipsilateral side of the spinal cord on day 7 after SNI ( ). In line with the flow cytometry result, immunofluorescence revealed a marked increase in the number of TRPV4-eGFP + cells co...
SNI upregulated TRPV4 expression in the spinal cord resident microglia.
Interestingly, none of the TRPV4-eGFP + cells expressed CCR2 ( ), suggesting that TRPV4-eGFP + cells are a subpopulation of spinal resident microglia but not infiltrated blood-borne monocytes. Given that the contribution of infiltrating monocytes to nerve injury-induced microgliosis is still an area of controversy, we further verified whether there was an infiltration of TRPV4-expressing blood-borne monocytes in the spinal dorsal horn in response to SNI. We first crossed a double-transgenic Trpv4 eGFP: Ccr2 RFP/+ line and Trpv4 eGFP: Ccr2 CreER/+:tdTomato line bearing eGFP-labeled TRPV4 + cells and RFP/tdTomato-labeled CCR2 + monocytes and observed no infiltrated CCR2 + /IBA1 + monocytes or CCR2 + /TRPV4 + cells in the spinal dorsal horn on day 7 after SNI ( and ), which is consistent with our flow cytometry observation. Additionally, to exclude the possibility of infiltratin...
SNI upregulated TRPV4 expression in the spinal cord resident microglia.
Next, we performed i.p. injections of 5-ethynyl-20-deoxyuridine (EdU) to the Trpv4 eGFP mice following SNI surgery. As expected, most of the EdU + microglia in the ipsilateral side of the spinal dorsal horn on day 7 after SNI were eGFP + ( ). Collectively, these findings indicate that the increased number of the TRPV4-eGFP + cells in the ipsilateral side of the dorsal horn following SNI was due to the proliferation of resident microglia rather than the infiltration of blood-borne monocytes.
Spinal activation of TRPV4 was sufficient to promote excitatory neuronal hyperactivity and produce acute mechanical p...
Bidirectional microglia-neuron communications are critical to the generation and maintenance of neuropathic pain (, ). We reasoned that if TRPV4 was a critical mediator of SNI-induced mechanical allodynia and microglial activation, direct chemical activation of spinal TRPV4 alone should be sufficient to cause pain hypersensitivity. Indeed, a single i.t. injection of GSK101 markedly reduced the paw-withdrawal threshold, which was reversed by coapplied GSK219 ( ). Moreover, GSK101-induced mechanical allodynia was significantly abolished in global Trpv4 KO mice ( ) and microglia-specific Trpv4 cKO mice ( ), but not in endothelial cell-specific or neuron-specific Trpv4 cKO mice ( and ). Interestingly, the mechanical hypersensitivity induced by i.t. application of GSK101 was reversible between 24-48 hours after injection, suggesting an acute and reversible activation/sensitization o...
Methods
Adult (8-12 weeks) male and/or female C57BL/6J mice (The Jackson Laboratory), Trpv4 eGFP (The Mutant Mouse Resource and Research Center [MMRRC]), Trpv4 -/- (donated by Makoto Suzuki and Atsuko Mizuno [Jichi Medical School, Minamikawachi, Tochigi, Japan]), Trpv4 flox ( ), Cx3cr1 CreER (The Jackson Laboratory), Tmem119 CreER (The Jackson Laboratory), tdTomato (Ai9, The Jackson Laboratory), GCaMP6s (Ai96, The Jackson Laboratory), Cx3cr1 GFP (The Jackson Laboratory), Ccr2 RFP (The Jackson Laboratory), Ccr2 CreER (provided in-house), Trpv1 Cre (donated by Mark Hoon [National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA]), Cdh5 Cre (The Jackson Laboratory), Vglut2 Cre (The Jackson Laboratory), Vgat Cre (The Jackson Laboratory), Lcn2 -/- (The Jackson Laboratory), and Lcn2 flox (donated by Jack Cowland [Rigshospitalet, Copenhagen, Denmar...
Microglia-expressed TRPV4 was necessary for SNI-induced functional and structural plasticity of spinal excitatory neu...
Given that central sensitization also depends on the structural plasticity of spinal neurons in chronic pain states ( ), we sought to investigate whether peripheral nerve injury induced dendrite spine remodeling beyond functional plasticity in the spinal neurons and whether it relies on the function of microglia-expressed TRPV4. Indeed, neurons in spinal lamina IIo stained by microinjection of biocytin exhibited a significant increase in the density of dendrite spines on day 7 after SNI compared with neurons from the sham control mice (, A and B). This SNI-induced increase in dendrite spine density was reduced in both global Trpv4 KO (, C and D) and microglia-specific Trpv4 cKO (, E and F) mice, as well as mice treated with repeated i.p. injections of GSK219 for 7 days after SNI (, G and H) when compared with their respective controls. These findings demonstrate that the transitio...
Microglia-expressed TRPV4 mediated functional and structural plasticity of spinal excitatory neurons through LCN2.
Microglia communicate with other cell types in the CNS by releasing soluble factors (, ). We showed that many proinflammatory cytokines can be released from activated microglia after SNI (, A-E). Notably, published studies demonstrated that immune cell-derived proinflammatory cytokines generally either modulate or have no effect on dendritic spine density in the CNS ( - ). Interestingly, we found that TRPV4 activation in microglia also markedly upregulated the production of LCN2, a secreted protein that was shown to be an important regulator of neuronal excitability in the CNS (,, ). Further, LCN2 expression is significantly upregulated in a mouse model of chronic neuropathic pain caused by spinal nerve ligation ( ). Importantly, LCN2 expression and function are closely related to spine density and membrane excitability in the CNS in a region-specific manner (, ), pro...
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Although sensory TRP channels are generally considered critical molecular sensors for mechanical, thermal, and chemical cues and contribute to both pain and itch sensations (, - ), the role of centrally expressed TRPV4 in neuropathic pain remains poorly understood. To test this possibility, we generated a well-established mouse model of SNI ( ) in both Trpv4 -/- (global Trpv4 KO) and congenic WT C57BL/6J mice. Strikingly, compared with WT mice, Trpv4 -/- mice had a significantly improved paw withdrawal threshold, a hallmark of mechanical allodynia, in both male and female mice following SNI ( ). To complement genetic ablation studies, we administered TRPV4 antagonist GSK219 once daily through repeated i.p. injections for 7 consecutive days starting on day 1 after SNI in WT mice and observed a marked increase in paw withdrawal threshold in a dose- and time-dependent manner ( ). Moreover, acute application of GSK219 through a single intrathecal (i.t.) injection on day 7 after SNI also produced a time- and dose-dependent attenuation of the decreased paw withdrawal threshold caused by SNI ( ), suggesting that TRPV4 in the spinal cord is involved in bot...
Next, we investigated how SNI affects TRPV4 expression in the spinal cord. Compared with naive or sham mice, Trpv4 mRNA transcripts were substantially upregulated in the ipsilateral side of the spinal dorsal horn starting within 1 day and lasting for at least 14 days after SNI ( ). RNAscope assay further revealed the presence of Trpv4 mRNA transcripts in CX3CR1 + microglia in the spinal cord of Cx3cr1 CreER/+:tdTomato mice on day 7 after SNI ( ). Moreover, flow cytometric analysis using Trpv4 eGFP mice with CD11b + CD45 + gating strategy revealed that,compared with the contralateral side, the number of TRPV4-eGFP + CX3CR1 + - but not TRPV4-eGFP + CCR2 + - cells was markedly increased in the ipsilateral side of the spinal cord on day 7 after SNI ( ). In line with the flow cytometry result, immunofluorescence revealed a marked increase in the number of TRPV4-eGFP + cells coexpressing IBA1 or CD31 in the ipsilateral side of the spinal cord on day 7 after SNI ( ). Of note, TRPV4-eGFP signals were only increased in IBA1 + microglia, but not in CD31 + endothelial cells ( ). We also crossed the Trpv4 eGFP mice with the Cx3cr1 CreER/+:tdTomato ( ) or Tmem119 CreER/+:tdTom...
Interestingly, none of the TRPV4-eGFP + cells expressed CCR2 ( ), suggesting that TRPV4-eGFP + cells are a subpopulation of spinal resident microglia but not infiltrated blood-borne monocytes. Given that the contribution of infiltrating monocytes to nerve injury-induced microgliosis is still an area of controversy, we further verified whether there was an infiltration of TRPV4-expressing blood-borne monocytes in the spinal dorsal horn in response to SNI. We first crossed a double-transgenic Trpv4 eGFP: Ccr2 RFP/+ line and Trpv4 eGFP: Ccr2 CreER/+:tdTomato line bearing eGFP-labeled TRPV4 + cells and RFP/tdTomato-labeled CCR2 + monocytes and observed no infiltrated CCR2 + /IBA1 + monocytes or CCR2 + /TRPV4 + cells in the spinal dorsal horn on day 7 after SNI ( and ), which is consistent with our flow cytometry observation. Additionally, to exclude the possibility of infiltrating CX3CR1 + monocytes in the spinal cord in response to peripheral nerve injury, we treated the Cx3cr1 CreER/+:tdTomato reporter mice with tamoxifen to label all CX3CR1 + myeloid cell populations, including spinal resident microglia and blood-borne monocytes. As the cell turnover rates differ betwee...
Next, we performed i.p. injections of 5-ethynyl-20-deoxyuridine (EdU) to the Trpv4 eGFP mice following SNI surgery. As expected, most of the EdU + microglia in the ipsilateral side of the spinal dorsal horn on day 7 after SNI were eGFP + ( ). Collectively, these findings indicate that the increased number of the TRPV4-eGFP + cells in the ipsilateral side of the dorsal horn following SNI was due to the proliferation of resident microglia rather than the infiltration of blood-borne monocytes.
Bidirectional microglia-neuron communications are critical to the generation and maintenance of neuropathic pain (, ). We reasoned that if TRPV4 was a critical mediator of SNI-induced mechanical allodynia and microglial activation, direct chemical activation of spinal TRPV4 alone should be sufficient to cause pain hypersensitivity. Indeed, a single i.t. injection of GSK101 markedly reduced the paw-withdrawal threshold, which was reversed by coapplied GSK219 ( ). Moreover, GSK101-induced mechanical allodynia was significantly abolished in global Trpv4 KO mice ( ) and microglia-specific Trpv4 cKO mice ( ), but not in endothelial cell-specific or neuron-specific Trpv4 cKO mice ( and ). Interestingly, the mechanical hypersensitivity induced by i.t. application of GSK101 was reversible between 24-48 hours after injection, suggesting an acute and reversible activation/sensitization of pain-transmitting neurons in the spinal cord.
Adult (8-12 weeks) male and/or female C57BL/6J mice (The Jackson Laboratory), Trpv4 eGFP (The Mutant Mouse Resource and Research Center [MMRRC]), Trpv4 -/- (donated by Makoto Suzuki and Atsuko Mizuno [Jichi Medical School, Minamikawachi, Tochigi, Japan]), Trpv4 flox ( ), Cx3cr1 CreER (The Jackson Laboratory), Tmem119 CreER (The Jackson Laboratory), tdTomato (Ai9, The Jackson Laboratory), GCaMP6s (Ai96, The Jackson Laboratory), Cx3cr1 GFP (The Jackson Laboratory), Ccr2 RFP (The Jackson Laboratory), Ccr2 CreER (provided in-house), Trpv1 Cre (donated by Mark Hoon [National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA]), Cdh5 Cre (The Jackson Laboratory), Vglut2 Cre (The Jackson Laboratory), Vgat Cre (The Jackson Laboratory), Lcn2 -/- (The Jackson Laboratory), and Lcn2 flox (donated by Jack Cowland [Rigshospitalet, Copenhagen, Denmark], Bin Gao [National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA], and Grace Guo [Rutgers University, Piscataway, New Jersey, USA]) mice were used for this study. Mice were bred and maintained (3-5 mice per cage) in individually ventilated cages on a 12 hour light/12 ho...
Given that central sensitization also depends on the structural plasticity of spinal neurons in chronic pain states ( ), we sought to investigate whether peripheral nerve injury induced dendrite spine remodeling beyond functional plasticity in the spinal neurons and whether it relies on the function of microglia-expressed TRPV4. Indeed, neurons in spinal lamina IIo stained by microinjection of biocytin exhibited a significant increase in the density of dendrite spines on day 7 after SNI compared with neurons from the sham control mice (, A and B). This SNI-induced increase in dendrite spine density was reduced in both global Trpv4 KO (, C and D) and microglia-specific Trpv4 cKO (, E and F) mice, as well as mice treated with repeated i.p. injections of GSK219 for 7 days after SNI (, G and H) when compared with their respective controls. These findings demonstrate that the transition of synaptic potentiation to structural alteration in the spinal cord pain circuit was dependent on the function of microglia-expressed TRPV4, which may underlie pain chronicity.
Microglia communicate with other cell types in the CNS by releasing soluble factors (, ). We showed that many proinflammatory cytokines can be released from activated microglia after SNI (, A-E). Notably, published studies demonstrated that immune cell-derived proinflammatory cytokines generally either modulate or have no effect on dendritic spine density in the CNS ( - ). Interestingly, we found that TRPV4 activation in microglia also markedly upregulated the production of LCN2, a secreted protein that was shown to be an important regulator of neuronal excitability in the CNS (,, ). Further, LCN2 expression is significantly upregulated in a mouse model of chronic neuropathic pain caused by spinal nerve ligation ( ). Importantly, LCN2 expression and function are closely related to spine density and membrane excitability in the CNS in a region-specific manner (, ), prompting us to hypothesize that LCN2 may be involved in TRPV4-mediated spinal synaptic plasticity and neuropathic pain. To test this hypothesis, we first checked LCN2 expression in the spinal cord and determined the role of TRPV4 in LCN2 production. Following SNI, LCN2 was specifically expressed in th...
Machine-readable layer
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"text": "Adult (8-12 weeks) male and/or female C57BL/6J mice (The Jackson Laboratory), Trpv4 eGFP (The Mutant Mouse Resource and Research Center [MMRRC]), Trpv4 -/- (donated by Makoto Suzuki and Atsuko Mizuno [Jichi Medical School, Minamikawachi, Tochigi, Japan]), Trpv4 flox ( ), Cx3cr1 CreER (The Jackson Laboratory), Tmem119 CreER (The Jackson Laboratory), tdTomato (Ai9, The Jackson Laboratory), GCaMP6s (Ai96, The Jackson Laboratory), Cx3cr1 GFP (The Jackson Laboratory), Ccr2 RFP (The Jackson Laboratory), Ccr2 CreER (provided in-house), Trpv1 Cre (donated by Mark Hoon [National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA]), Cdh5 Cre (The Jackson Laboratory), Vglut2 Cre (The Jackson Laboratory), Vgat Cre (The Jackson Laboratory), Lcn2 -/- (The Jackson Laboratory), and Lcn2 flox (donated by Jack Cowland [Rigshospitalet, Copenhagen, Denmar..."
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"datePublished": "2023",
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"identifier": "10.1172/jci161507"
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