Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model
Abstract Background Central sensitization is an important mechanism of chronic migraine (CM) and is related to the inflammatory response of microglia. The NOD-like receptor protein 3 (NLRP3) inflammasome may regulate the inflammatory process of microglia in several neurological diseases, but its rol...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-04-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-019-1459-7 |
| _version_ | 1811198623522750464 |
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| author | Wei He Ting Long Qi Pan Shanshan Zhang Yixin Zhang Dunke Zhang Guangcheng Qin Lixue Chen Jiying Zhou |
| author_facet | Wei He Ting Long Qi Pan Shanshan Zhang Yixin Zhang Dunke Zhang Guangcheng Qin Lixue Chen Jiying Zhou |
| author_sort | Wei He |
| collection | DOAJ |
| description | Abstract Background Central sensitization is an important mechanism of chronic migraine (CM) and is related to the inflammatory response of microglia. The NOD-like receptor protein 3 (NLRP3) inflammasome may regulate the inflammatory process of microglia in several neurological diseases, but its role in CM is largely unknown. Therefore, the aim of this study was to identify the precise role of microglial NLRP3 in CM. Methods An experimental CM mouse model was established by repeated intraperitoneal (i.p) injection with nitroglycerin (NTG). We evaluated the expression levels of NLRP3 and its downstream interleukin (IL)-1β protein in the trigeminal nucleus caudalis (TNC; which is a central area relevant to migraine pain) at different time points. To further examine the effects of the NLRP3 inflammasome pathway on central sensitization of CM, we examined MCC950, an NLRP3 inflammasome-specific inhibitor, and IL-1ra, an IL-1β antagonist, whether altered NTG-induced mechanical hyperalgesia of the periorbital area and hind paw. The effect of MCC950 and IL-1ra on c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK) and calcitonin gene-related peptide (CGRP) expression in the TNC were also analyzed. The cell localization of NLRP3 and IL-1β in the TNC was evaluated by immunofluorescence staining. Results Repeated NTG administration induced acute and chronic mechanical hyperalgesia and increased expression of NLRP3 and IL-1β. Blockade of NLRP3 or IL-1β reduced NTG-induced hyperalgesia, and this effect was accompanied by a significant inhibition of the NTG-induced increase in p-ERK, c-Fos and CGRP levels in the TNC. Immunofluorescence staining revealed that NLRP3 and IL-1β were mainly expressed in microglia in the TNC, and the IL-1β receptor, IL-1R, was mainly expressed in neurons in the TNC. Conclusions These results indicate that NLRP3 activation in the TNC participates in the microglial-neuronal signal by mediating the inflammatory response. This process contributes to the central sensitization observed in CM. |
| first_indexed | 2024-04-12T01:34:30Z |
| format | Article |
| id | doaj.art-d64d05b7830e47f68ecd9a5f44853977 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-12T01:34:30Z |
| publishDate | 2019-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-d64d05b7830e47f68ecd9a5f448539772022-12-22T03:53:23ZengBMCJournal of Neuroinflammation1742-20942019-04-0116111710.1186/s12974-019-1459-7Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine modelWei He0Ting Long1Qi Pan2Shanshan Zhang3Yixin Zhang4Dunke Zhang5Guangcheng Qin6Lixue Chen7Jiying Zhou8Department of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityLaboratory Research Center, The First Affiliated Hospital of Chongqing Medical UniversityLaboratory Research Center, The First Affiliated Hospital of Chongqing Medical UniversityLaboratory Research Center, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityAbstract Background Central sensitization is an important mechanism of chronic migraine (CM) and is related to the inflammatory response of microglia. The NOD-like receptor protein 3 (NLRP3) inflammasome may regulate the inflammatory process of microglia in several neurological diseases, but its role in CM is largely unknown. Therefore, the aim of this study was to identify the precise role of microglial NLRP3 in CM. Methods An experimental CM mouse model was established by repeated intraperitoneal (i.p) injection with nitroglycerin (NTG). We evaluated the expression levels of NLRP3 and its downstream interleukin (IL)-1β protein in the trigeminal nucleus caudalis (TNC; which is a central area relevant to migraine pain) at different time points. To further examine the effects of the NLRP3 inflammasome pathway on central sensitization of CM, we examined MCC950, an NLRP3 inflammasome-specific inhibitor, and IL-1ra, an IL-1β antagonist, whether altered NTG-induced mechanical hyperalgesia of the periorbital area and hind paw. The effect of MCC950 and IL-1ra on c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK) and calcitonin gene-related peptide (CGRP) expression in the TNC were also analyzed. The cell localization of NLRP3 and IL-1β in the TNC was evaluated by immunofluorescence staining. Results Repeated NTG administration induced acute and chronic mechanical hyperalgesia and increased expression of NLRP3 and IL-1β. Blockade of NLRP3 or IL-1β reduced NTG-induced hyperalgesia, and this effect was accompanied by a significant inhibition of the NTG-induced increase in p-ERK, c-Fos and CGRP levels in the TNC. Immunofluorescence staining revealed that NLRP3 and IL-1β were mainly expressed in microglia in the TNC, and the IL-1β receptor, IL-1R, was mainly expressed in neurons in the TNC. Conclusions These results indicate that NLRP3 activation in the TNC participates in the microglial-neuronal signal by mediating the inflammatory response. This process contributes to the central sensitization observed in CM.http://link.springer.com/article/10.1186/s12974-019-1459-7Chronic migraineNod-like receptor protein 3 inflammasomeInterleukin-1βCentral sensitization |
| spellingShingle | Wei He Ting Long Qi Pan Shanshan Zhang Yixin Zhang Dunke Zhang Guangcheng Qin Lixue Chen Jiying Zhou Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model Journal of Neuroinflammation Chronic migraine Nod-like receptor protein 3 inflammasome Interleukin-1β Central sensitization |
| title | Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model |
| title_full | Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model |
| title_fullStr | Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model |
| title_full_unstemmed | Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model |
| title_short | Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model |
| title_sort | microglial nlrp3 inflammasome activation mediates il 1β release and contributes to central sensitization in a recurrent nitroglycerin induced migraine model |
| topic | Chronic migraine Nod-like receptor protein 3 inflammasome Interleukin-1β Central sensitization |
| url | http://link.springer.com/article/10.1186/s12974-019-1459-7 |
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