TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc
Abstract Background The ion channel transient receptor potential vanilloid 4 (TRPV4) critically transduces mechanical forces in the IVD, and its inhibition can prevent IVD degeneration due to static overloading. However, it remains unknown whether different modes of loading signals through TRPV4 to...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-12-01
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| Series: | JOR Spine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jsp2.1282 |
| _version_ | 1797374857171697664 |
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| author | Garrett W. D. Easson Alireza Savadipour Christian Gonzalez Farshid Guilak Simon Y. Tang |
| author_facet | Garrett W. D. Easson Alireza Savadipour Christian Gonzalez Farshid Guilak Simon Y. Tang |
| author_sort | Garrett W. D. Easson |
| collection | DOAJ |
| description | Abstract Background The ion channel transient receptor potential vanilloid 4 (TRPV4) critically transduces mechanical forces in the IVD, and its inhibition can prevent IVD degeneration due to static overloading. However, it remains unknown whether different modes of loading signals through TRPV4 to regulate the expression of inflammatory cytokines. We hypothesized that TRPV4 signaling is essential during static and dynamic loading to mediate homeostasis and mechanotransduction. Methods Mouse functional spine units were isolated and either cyclically compressed for 5 days (1 Hz, 1 h, 10% strain) or statically compressed (24 h, 0.2 MPa). Conditioned media were monitored at 6 h, 24 h, 2 days, and 5 days, with and without TRPV4 inhibition. Effects of TRPV4 activation was also evaluated without loading. The media was analyzed for a panel of 44 cytokines using a microbead array and then a correlative network was constructed to explore the regulatory relationships during loading and TRPV4 inhibition. After the loading regimen, the IVDs were evaluated histologically for degeneration. Results Activation of TRPV4 led to an increase interleukin‐6 (IL‐6) family of cytokines (IL‐6, IL‐11, IL‐16, and leukemia inhibitory factor [LIF]) and decreased the T‐cell (CCL3, CCL4, CCL17, CCL20, CCL22, and CXCL10) and monocyte (CCL2 and CCL12) recruiting chemokines by the IVD. Dynamic and static loading each provoked unique chemokine correlation networks. The inhibition of TRPV4 during dynamic loading dysregulated the relationship between LIF and other cytokines, while the inhibition of TRPV4 during static loading disrupted the connectivity of IL‐16 and VEGFA. Conclusions We demonstrated that TRPV4 critically mediates the cytokine production following dynamic and static loading. The activation of TRPV4 upregulated a diverse set of cytokines that may suppress the chemotaxis of T‐cells and monocytes, implicating the role of TRPV4 in maintaining the immune privilege of healthy IVD. |
| first_indexed | 2024-03-08T19:11:50Z |
| format | Article |
| id | doaj.art-a079bb713e43442380654a2c6a68a239 |
| institution | Directory Open Access Journal |
| issn | 2572-1143 |
| language | English |
| last_indexed | 2024-03-08T19:11:50Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | JOR Spine |
| spelling | doaj.art-a079bb713e43442380654a2c6a68a2392023-12-27T12:34:04ZengWileyJOR Spine2572-11432023-12-0164n/an/a10.1002/jsp2.1282TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral discGarrett W. D. Easson0Alireza Savadipour1Christian Gonzalez2Farshid Guilak3Simon Y. Tang4Department of Orthopaedic Surgery Washington University in St. Louis St. Louis Missouri USADepartment of Orthopaedic Surgery Washington University in St. Louis St. Louis Missouri USADepartment of Biomedical Engineering Washington University in St. Louis St. Louis Missouri USADepartment of Orthopaedic Surgery Washington University in St. Louis St. Louis Missouri USADepartment of Orthopaedic Surgery Washington University in St. Louis St. Louis Missouri USAAbstract Background The ion channel transient receptor potential vanilloid 4 (TRPV4) critically transduces mechanical forces in the IVD, and its inhibition can prevent IVD degeneration due to static overloading. However, it remains unknown whether different modes of loading signals through TRPV4 to regulate the expression of inflammatory cytokines. We hypothesized that TRPV4 signaling is essential during static and dynamic loading to mediate homeostasis and mechanotransduction. Methods Mouse functional spine units were isolated and either cyclically compressed for 5 days (1 Hz, 1 h, 10% strain) or statically compressed (24 h, 0.2 MPa). Conditioned media were monitored at 6 h, 24 h, 2 days, and 5 days, with and without TRPV4 inhibition. Effects of TRPV4 activation was also evaluated without loading. The media was analyzed for a panel of 44 cytokines using a microbead array and then a correlative network was constructed to explore the regulatory relationships during loading and TRPV4 inhibition. After the loading regimen, the IVDs were evaluated histologically for degeneration. Results Activation of TRPV4 led to an increase interleukin‐6 (IL‐6) family of cytokines (IL‐6, IL‐11, IL‐16, and leukemia inhibitory factor [LIF]) and decreased the T‐cell (CCL3, CCL4, CCL17, CCL20, CCL22, and CXCL10) and monocyte (CCL2 and CCL12) recruiting chemokines by the IVD. Dynamic and static loading each provoked unique chemokine correlation networks. The inhibition of TRPV4 during dynamic loading dysregulated the relationship between LIF and other cytokines, while the inhibition of TRPV4 during static loading disrupted the connectivity of IL‐16 and VEGFA. Conclusions We demonstrated that TRPV4 critically mediates the cytokine production following dynamic and static loading. The activation of TRPV4 upregulated a diverse set of cytokines that may suppress the chemotaxis of T‐cells and monocytes, implicating the role of TRPV4 in maintaining the immune privilege of healthy IVD.https://doi.org/10.1002/jsp2.1282degenerationdynamic compressioninflammatory cytokine networksintervertebral discstatic compressionTRPV4 |
| spellingShingle | Garrett W. D. Easson Alireza Savadipour Christian Gonzalez Farshid Guilak Simon Y. Tang TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc JOR Spine degeneration dynamic compression inflammatory cytokine networks intervertebral disc static compression TRPV4 |
| title | TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc |
| title_full | TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc |
| title_fullStr | TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc |
| title_full_unstemmed | TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc |
| title_short | TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc |
| title_sort | trpv4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc |
| topic | degeneration dynamic compression inflammatory cytokine networks intervertebral disc static compression TRPV4 |
| url | https://doi.org/10.1002/jsp2.1282 |
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