Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice
Abstract Background Major depressive disorder (MDD) is a common but severe psychiatric illness characterized by depressive mood and diminished interest. Both nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 1 (NLRP1) inflammasome and autophagy have been repo...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-023-02995-4 |
| _version_ | 1797363056417701888 |
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| author | Ya-Jing Zhu Jing Huang Ru Chen Yu Zhang Xin He Wen-Xin Duan Yuan-Lei Zou Meng-Mei Sun Hui-Li Sun Si-Min Cheng Hao-Chuan Wang Hao Zhang Wen-Ning Wu |
| author_facet | Ya-Jing Zhu Jing Huang Ru Chen Yu Zhang Xin He Wen-Xin Duan Yuan-Lei Zou Meng-Mei Sun Hui-Li Sun Si-Min Cheng Hao-Chuan Wang Hao Zhang Wen-Ning Wu |
| author_sort | Ya-Jing Zhu |
| collection | DOAJ |
| description | Abstract Background Major depressive disorder (MDD) is a common but severe psychiatric illness characterized by depressive mood and diminished interest. Both nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 1 (NLRP1) inflammasome and autophagy have been reported to implicate in the pathological processes of depression. However, the mechanistic interplay between NLRP1 inflammasome, autophagy, and depression is still poorly known. Methods Animal model of depression was established by chronic social defeat stress (CSDS). Depressive-like behaviors were determined by social interaction test (SIT), sucrose preference test (SPT), open field test (OFT), forced swim test (FST), and tail-suspension test (TST). The protein expression levels of NLRP1 inflammasome complexes, pro-inflammatory cytokines, phosphorylated-phosphatidylinositol 3-kinase (p-PI3K)/PI3K, phosphorylated-AKT (p-AKT)/AKT, phosphorylated-mechanistic target of rapamycin (p-mTOR)/mTOR, brain-derived neurotrophic factor (BDNF), phosphorylated-tyrosine kinase receptor B (p-TrkB)/TrkB, Bcl-2-associated X protein (Bax)/B-cell lymphoma-2 (Bcl2) and cleaved cysteinyl aspartate-specific proteinase-3 (caspase-3) were examined by western blotting. The mRNA expression levels of pro-inflammatory cytokines were tested by quantitative real-time PCR. The interaction between proteins was detected by immunofluorescence and coimmunoprecipitation. Neuronal injury was assessed by Nissl staining. The autophagosomes were visualized by transmission electron microscopy. Nlrp1a knockdown was performed using an adeno-associated virus (AAV) vector containing Nlrp1a–shRNA–eGFP infusion. Results CSDS exposure caused a bidirectional change in hippocampal autophagy function, which was activated in the initial period but impaired at the later stage. In addition, CSDS exposure increased the expression levels of hippocampal NLRP1 inflammasome complexes, pro-inflammatory cytokines, p-PI3K, p-AKT and p-mTOR in a time-dependent manner. Interestingly, NLRP1 is immunoprecipitated with mTOR but not PI3K/AKT and CSDS exposure facilitated the immunoprecipitation between them. Hippocampal Nlrp1a knockdown inhibited the activity of PI3K/AKT/mTOR signaling, rescued the impaired autophagy and ameliorated depressive-like behavior induced by CSDS. In addition, rapamycin, an autophagy inducer, abolished NLRP1 inflammasome-driven inflammatory reactions, alleviated depressive-like behavior and exerted a neuroprotective effect. Conclusions Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behavior in mice and the regulation of autophagy could be a valuable therapeutic strategy for the management of depression. |
| first_indexed | 2024-03-08T16:15:19Z |
| format | Article |
| id | doaj.art-7702e912c69a43bbabea0f8f53f7898b |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-08T16:15:19Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-7702e912c69a43bbabea0f8f53f7898b2024-01-07T12:37:16ZengBMCJournal of Neuroinflammation1742-20942024-01-0121111710.1186/s12974-023-02995-4Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in miceYa-Jing Zhu0Jing Huang1Ru Chen2Yu Zhang3Xin He4Wen-Xin Duan5Yuan-Lei Zou6Meng-Mei Sun7Hui-Li Sun8Si-Min Cheng9Hao-Chuan Wang10Hao Zhang11Wen-Ning Wu12Department of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityDepartment of Oncology, the First Affiliated Hospital of Anhui Medical UniversityDepartment of Pharmacology & Research Centre for Neurological Disorders, School of Basic Medical Sciences, Anhui Medical UniversityAbstract Background Major depressive disorder (MDD) is a common but severe psychiatric illness characterized by depressive mood and diminished interest. Both nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 1 (NLRP1) inflammasome and autophagy have been reported to implicate in the pathological processes of depression. However, the mechanistic interplay between NLRP1 inflammasome, autophagy, and depression is still poorly known. Methods Animal model of depression was established by chronic social defeat stress (CSDS). Depressive-like behaviors were determined by social interaction test (SIT), sucrose preference test (SPT), open field test (OFT), forced swim test (FST), and tail-suspension test (TST). The protein expression levels of NLRP1 inflammasome complexes, pro-inflammatory cytokines, phosphorylated-phosphatidylinositol 3-kinase (p-PI3K)/PI3K, phosphorylated-AKT (p-AKT)/AKT, phosphorylated-mechanistic target of rapamycin (p-mTOR)/mTOR, brain-derived neurotrophic factor (BDNF), phosphorylated-tyrosine kinase receptor B (p-TrkB)/TrkB, Bcl-2-associated X protein (Bax)/B-cell lymphoma-2 (Bcl2) and cleaved cysteinyl aspartate-specific proteinase-3 (caspase-3) were examined by western blotting. The mRNA expression levels of pro-inflammatory cytokines were tested by quantitative real-time PCR. The interaction between proteins was detected by immunofluorescence and coimmunoprecipitation. Neuronal injury was assessed by Nissl staining. The autophagosomes were visualized by transmission electron microscopy. Nlrp1a knockdown was performed using an adeno-associated virus (AAV) vector containing Nlrp1a–shRNA–eGFP infusion. Results CSDS exposure caused a bidirectional change in hippocampal autophagy function, which was activated in the initial period but impaired at the later stage. In addition, CSDS exposure increased the expression levels of hippocampal NLRP1 inflammasome complexes, pro-inflammatory cytokines, p-PI3K, p-AKT and p-mTOR in a time-dependent manner. Interestingly, NLRP1 is immunoprecipitated with mTOR but not PI3K/AKT and CSDS exposure facilitated the immunoprecipitation between them. Hippocampal Nlrp1a knockdown inhibited the activity of PI3K/AKT/mTOR signaling, rescued the impaired autophagy and ameliorated depressive-like behavior induced by CSDS. In addition, rapamycin, an autophagy inducer, abolished NLRP1 inflammasome-driven inflammatory reactions, alleviated depressive-like behavior and exerted a neuroprotective effect. Conclusions Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behavior in mice and the regulation of autophagy could be a valuable therapeutic strategy for the management of depression.https://doi.org/10.1186/s12974-023-02995-4MDDNLRP1 inflammasomeAutophagyCSDSmTORPI3K/AKT |
| spellingShingle | Ya-Jing Zhu Jing Huang Ru Chen Yu Zhang Xin He Wen-Xin Duan Yuan-Lei Zou Meng-Mei Sun Hui-Li Sun Si-Min Cheng Hao-Chuan Wang Hao Zhang Wen-Ning Wu Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice Journal of Neuroinflammation MDD NLRP1 inflammasome Autophagy CSDS mTOR PI3K/AKT |
| title | Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice |
| title_full | Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice |
| title_fullStr | Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice |
| title_full_unstemmed | Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice |
| title_short | Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice |
| title_sort | autophagy dysfunction contributes to nlrp1 inflammasome linked depressive like behaviors in mice |
| topic | MDD NLRP1 inflammasome Autophagy CSDS mTOR PI3K/AKT |
| url | https://doi.org/10.1186/s12974-023-02995-4 |
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