Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice
Spinal microglia and astrocytes are both involved in neuropathic and inflammatory pain, which may display sexual dimorphism. Here, we demonstrate that the sustained activation of spinal astrocytes and astrocyte-derived interleukin (IL)-17A promotes the progression of mouse bone cancer pain without s...
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| Format: | Article |
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Elsevier
2024-12-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383524003812 |
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| author | Huizhu Liu Xuejing Lv Xin Zhao Lanxing Yi Ning Lv Wendong Xu Yuqiu Zhang |
| author_facet | Huizhu Liu Xuejing Lv Xin Zhao Lanxing Yi Ning Lv Wendong Xu Yuqiu Zhang |
| author_sort | Huizhu Liu |
| collection | DOAJ |
| description | Spinal microglia and astrocytes are both involved in neuropathic and inflammatory pain, which may display sexual dimorphism. Here, we demonstrate that the sustained activation of spinal astrocytes and astrocyte-derived interleukin (IL)-17A promotes the progression of mouse bone cancer pain without sex differences. Chemogenetic or pharmacological inhibition of spinal astrocytes effectively ameliorates bone cancer-induced pain-like behaviors. In contrast, chemogenetic or optogenetic activation of spinal astrocytes triggers pain hypersensitivity, implying that bone cancer-induced astrocytic activation is involved in the development of bone cancer pain. IL-17A expression predominantly in spinal astrocytes, whereas its receptor IL-17 receptor A (IL-17RA) was mainly detected in neurons expressing VGLUT2 and PAX2, and a few in astrocytes expressing GFAP. Specific knockdown of IL-17A in spinal astrocytes blocked and delayed the development of bone cancer pain. IL-17A overexpression in spinal astrocytes directly induced thermal hyperalgesia and mechanical allodynia, which could be rescued by CaMKIIα inhibitor. Moreover, selective knockdown IL-17RA in spinal Vglut2+ or Vgat+neurons, but not in astrocytes, significantly blocked the bone cancer-induced hyperalgesia. Together, our findings provide evidence for the crucial role of sex-independent astrocytic signaling in bone cancer pain. Targeting spinal astrocytes and IL-17A/IL-17RA-CaMKIIα signaling may offer new gender-inclusive therapeutic strategies for managing bone cancer pain. |
| format | Article |
| id | doaj-art-fae11f272a9f4e009a22c8632b8c69f4 |
| institution | Kabale University |
| issn | 2211-3835 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-fae11f272a9f4e009a22c8632b8c69f42024-12-18T08:48:46ZengElsevierActa Pharmaceutica Sinica B2211-38352024-12-01141252495266Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer miceHuizhu Liu0Xuejing Lv1Xin Zhao2Lanxing Yi3Ning Lv4Wendong Xu5Yuqiu Zhang6Department of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, ChinaDepartment of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, ChinaDepartment of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, ChinaDepartment of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, ChinaDepartment of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; Corresponding authors.Department of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China; Corresponding authors.Department of Translational Neuroscience, Jing’an District Centre Hospital of Shanghai, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; Corresponding authors.Spinal microglia and astrocytes are both involved in neuropathic and inflammatory pain, which may display sexual dimorphism. Here, we demonstrate that the sustained activation of spinal astrocytes and astrocyte-derived interleukin (IL)-17A promotes the progression of mouse bone cancer pain without sex differences. Chemogenetic or pharmacological inhibition of spinal astrocytes effectively ameliorates bone cancer-induced pain-like behaviors. In contrast, chemogenetic or optogenetic activation of spinal astrocytes triggers pain hypersensitivity, implying that bone cancer-induced astrocytic activation is involved in the development of bone cancer pain. IL-17A expression predominantly in spinal astrocytes, whereas its receptor IL-17 receptor A (IL-17RA) was mainly detected in neurons expressing VGLUT2 and PAX2, and a few in astrocytes expressing GFAP. Specific knockdown of IL-17A in spinal astrocytes blocked and delayed the development of bone cancer pain. IL-17A overexpression in spinal astrocytes directly induced thermal hyperalgesia and mechanical allodynia, which could be rescued by CaMKIIα inhibitor. Moreover, selective knockdown IL-17RA in spinal Vglut2+ or Vgat+neurons, but not in astrocytes, significantly blocked the bone cancer-induced hyperalgesia. Together, our findings provide evidence for the crucial role of sex-independent astrocytic signaling in bone cancer pain. Targeting spinal astrocytes and IL-17A/IL-17RA-CaMKIIα signaling may offer new gender-inclusive therapeutic strategies for managing bone cancer pain.http://www.sciencedirect.com/science/article/pii/S2211383524003812AstrocyteMicrogliaInterleukin-17ASex differenceChemogenetic manipulationOptogenetic manipulation |
| spellingShingle | Huizhu Liu Xuejing Lv Xin Zhao Lanxing Yi Ning Lv Wendong Xu Yuqiu Zhang Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice Acta Pharmaceutica Sinica B Astrocyte Microglia Interleukin-17A Sex difference Chemogenetic manipulation Optogenetic manipulation |
| title | Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice |
| title_full | Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice |
| title_fullStr | Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice |
| title_full_unstemmed | Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice |
| title_short | Spinal astrocyte-derived interleukin-17A promotes pain hypersensitivity in bone cancer mice |
| title_sort | spinal astrocyte derived interleukin 17a promotes pain hypersensitivity in bone cancer mice |
| topic | Astrocyte Microglia Interleukin-17A Sex difference Chemogenetic manipulation Optogenetic manipulation |
| url | http://www.sciencedirect.com/science/article/pii/S2211383524003812 |
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