Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway
Abstract Background Microglia-derived lysosomal cathepsins are important inflammatory mediators to trigger signaling pathways in inflammation-related cascades. Our previous study showed that the expression of cathepsin C (CatC) in the brain is induced predominantly in activated microglia in neuroinf...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-01-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-019-1398-3 |
| _version_ | 1818486264350900224 |
|---|---|
| author | Qing Liu Yanli Zhang Shuang Liu Yanna Liu Xiaohan Yang Gang Liu Takahiro Shimizu Kazuhiro Ikenaka Kai Fan Jianmei Ma |
| author_facet | Qing Liu Yanli Zhang Shuang Liu Yanna Liu Xiaohan Yang Gang Liu Takahiro Shimizu Kazuhiro Ikenaka Kai Fan Jianmei Ma |
| author_sort | Qing Liu |
| collection | DOAJ |
| description | Abstract Background Microglia-derived lysosomal cathepsins are important inflammatory mediators to trigger signaling pathways in inflammation-related cascades. Our previous study showed that the expression of cathepsin C (CatC) in the brain is induced predominantly in activated microglia in neuroinflammation. Moreover, CatC can induce chemokine production in brain inflammatory processes. In vitro studies further confirmed that CatC is secreted extracellularly from LPS-treated microglia. However, the mechanisms of CatC affecting neuroinflammatory responses are not known yet. Methods CatC over-expression (CatCOE) and knock-down (CatCKD) mice were treated with intraperitoneal and intracerebroventricular LPS injection. Morris water maze (MWM) test was used to assess the ability of learning and memory. Cytokine expression in vivo was detected by in situ hybridization, quantitative PCR, and ELISA. In vitro, microglia M1 polarization was determined by quantitative PCR. Intracellular Ca2+ concentration was determined by flow cytometry, and the expression of NR2B, PKC, p38, IkBα, and p65 was determined by western blotting. Results The LPS-treated CatCOE mice exhibited significantly increased escape latency compared with similarly treated wild-type or CatCKD mice. The highest levels of TNF-α, IL-1β, and other M1 markers (IL-6, CD86, CD16, and CD32) were found in the brain or serum of LPS-treated CatCOE mice, and the lowest levels were detected in CatCKD mice. Similar results were found in LPS-treated microglia derived from CatC differentially expressing mice or in CatC-treated microglia from wild-type mice. Furthermore, the expression of NR2B mRNA, phosphorylation of NR2B, Ca2+ concentration, phosphorylation of PKC, p38, IκBα, and p65 were all increased in CatC-treated microglia, while addition of E-64 and MK-801 reversed the phosphorylation of above molecules. Conclusion The data suggest that CatC promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway. CatC may be one of key molecular targets for alleviating and controlling neuroinflammation in neurological diseases. |
| first_indexed | 2024-12-10T16:20:38Z |
| format | Article |
| id | doaj.art-0d1e62b7670343dc9d7533c2ff343b88 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-10T16:20:38Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-0d1e62b7670343dc9d7533c2ff343b882022-12-22T01:41:50ZengBMCJournal of Neuroinflammation1742-20942019-01-0116111810.1186/s12974-019-1398-3Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathwayQing Liu0Yanli Zhang1Shuang Liu2Yanna Liu3Xiaohan Yang4Gang Liu5Takahiro Shimizu6Kazuhiro Ikenaka7Kai Fan8Jianmei Ma9Department of Anatomy, Dalian Medical UniversityDepartment of Anatomy, Dalian Medical UniversityDepartment of Anatomy, Dalian Medical UniversityDepartment of Anatomy, Dalian Medical UniversityLiaoning Provincial Key Laboratory of Brain Diseases, Dalian Medical UniversityBasic Medicine College, Dalian Medical UniversityWolfson Institute for Biomedical Research, University College LondonDivision of Neurobiology and Bioinformatics, National Institute for Physiological SciencesDepartment of Anatomy, Dalian Medical UniversityDepartment of Anatomy, Dalian Medical UniversityAbstract Background Microglia-derived lysosomal cathepsins are important inflammatory mediators to trigger signaling pathways in inflammation-related cascades. Our previous study showed that the expression of cathepsin C (CatC) in the brain is induced predominantly in activated microglia in neuroinflammation. Moreover, CatC can induce chemokine production in brain inflammatory processes. In vitro studies further confirmed that CatC is secreted extracellularly from LPS-treated microglia. However, the mechanisms of CatC affecting neuroinflammatory responses are not known yet. Methods CatC over-expression (CatCOE) and knock-down (CatCKD) mice were treated with intraperitoneal and intracerebroventricular LPS injection. Morris water maze (MWM) test was used to assess the ability of learning and memory. Cytokine expression in vivo was detected by in situ hybridization, quantitative PCR, and ELISA. In vitro, microglia M1 polarization was determined by quantitative PCR. Intracellular Ca2+ concentration was determined by flow cytometry, and the expression of NR2B, PKC, p38, IkBα, and p65 was determined by western blotting. Results The LPS-treated CatCOE mice exhibited significantly increased escape latency compared with similarly treated wild-type or CatCKD mice. The highest levels of TNF-α, IL-1β, and other M1 markers (IL-6, CD86, CD16, and CD32) were found in the brain or serum of LPS-treated CatCOE mice, and the lowest levels were detected in CatCKD mice. Similar results were found in LPS-treated microglia derived from CatC differentially expressing mice or in CatC-treated microglia from wild-type mice. Furthermore, the expression of NR2B mRNA, phosphorylation of NR2B, Ca2+ concentration, phosphorylation of PKC, p38, IκBα, and p65 were all increased in CatC-treated microglia, while addition of E-64 and MK-801 reversed the phosphorylation of above molecules. Conclusion The data suggest that CatC promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway. CatC may be one of key molecular targets for alleviating and controlling neuroinflammation in neurological diseases.http://link.springer.com/article/10.1186/s12974-019-1398-3NeuroinflammationMicrogliaCathepsin CCytokineNR2B |
| spellingShingle | Qing Liu Yanli Zhang Shuang Liu Yanna Liu Xiaohan Yang Gang Liu Takahiro Shimizu Kazuhiro Ikenaka Kai Fan Jianmei Ma Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway Journal of Neuroinflammation Neuroinflammation Microglia Cathepsin C Cytokine NR2B |
| title | Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway |
| title_full | Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway |
| title_fullStr | Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway |
| title_full_unstemmed | Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway |
| title_short | Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway |
| title_sort | cathepsin c promotes microglia m1 polarization and aggravates neuroinflammation via activation of ca2 dependent pkc p38mapk nf κb pathway |
| topic | Neuroinflammation Microglia Cathepsin C Cytokine NR2B |
| url | http://link.springer.com/article/10.1186/s12974-019-1398-3 |
| work_keys_str_mv | AT qingliu cathepsincpromotesmicrogliam1polarizationandaggravatesneuroinflammationviaactivationofca2dependentpkcp38mapknfkbpathway AT yanlizhang cathepsincpromotesmicrogliam1polarizationandaggravatesneuroinflammationviaactivationofca2dependentpkcp38mapknfkbpathway AT shuangliu cathepsincpromotesmicrogliam1polarizationandaggravatesneuroinflammationviaactivationofca2dependentpkcp38mapknfkbpathway AT yannaliu cathepsincpromotesmicrogliam1polarizationandaggravatesneuroinflammationviaactivationofca2dependentpkcp38mapknfkbpathway AT xiaohanyang cathepsincpromotesmicrogliam1polarizationandaggravatesneuroinflammationviaactivationofca2dependentpkcp38mapknfkbpathway AT gangliu cathepsincpromotesmicrogliam1polarizationandaggravatesneuroinflammationviaactivationofca2dependentpkcp38mapknfkbpathway AT takahiroshimizu cathepsincpromotesmicrogliam1polarizationandaggravatesneuroinflammationviaactivationofca2dependentpkcp38mapknfkbpathway AT kazuhiroikenaka cathepsincpromotesmicrogliam1polarizationandaggravatesneuroinflammationviaactivationofca2dependentpkcp38mapknfkbpathway AT kaifan cathepsincpromotesmicrogliam1polarizationandaggravatesneuroinflammationviaactivationofca2dependentpkcp38mapknfkbpathway AT jianmeima cathepsincpromotesmicrogliam1polarizationandaggravatesneuroinflammationviaactivationofca2dependentpkcp38mapknfkbpathway |