Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice
Abstract Blood-brain barrier (BBB) disintegration is a key contributor to neuroinflammation; however, the biological processes governing BBB permeability under physiological conditions remain unclear. Here, we investigate the role of NLRP3 inflammasome in BBB disruption following peripheral inflamma...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56097-1 |
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| author | Sung-Hyun Yoon Chae youn Kim Eunju Lee Changjun Lee Kyung-Seo Lee Jaeho Lee Hana Park Bokeum Choi Inhwa Hwang Junhan Kim Tae-Gyun Kim Junghyun Son Young-Min Hyun Seunghee Hong Je-Wook Yu |
| author_facet | Sung-Hyun Yoon Chae youn Kim Eunju Lee Changjun Lee Kyung-Seo Lee Jaeho Lee Hana Park Bokeum Choi Inhwa Hwang Junhan Kim Tae-Gyun Kim Junghyun Son Young-Min Hyun Seunghee Hong Je-Wook Yu |
| author_sort | Sung-Hyun Yoon |
| collection | DOAJ |
| description | Abstract Blood-brain barrier (BBB) disintegration is a key contributor to neuroinflammation; however, the biological processes governing BBB permeability under physiological conditions remain unclear. Here, we investigate the role of NLRP3 inflammasome in BBB disruption following peripheral inflammatory challenges. Repeated intraperitoneal lipopolysaccharide administration causes NLRP3-dependent BBB permeabilization and myeloid cell infiltration into the brain. Using a mouse model with cell-specific hyperactivation of NLRP3, we identify microglial NLRP3 activation as essential for peripheral inflammation-induced BBB disruption. Conversely, NLRP3 and microglial gasdermin D (GSDMD) deficiency markedly attenuates lipopolysaccharide-induced BBB breakdown. Notably, IL-1β is not required for NLRP3-GSDMD-mediated BBB disruption. Instead, microglial NLRP3-GSDMD axis upregulates CXCL chemokines and matrix metalloproteinases around BBB via producing GDF-15, promoting the recruitment of CXCR2-containing neutrophils. Inhibition of neutrophil infiltration and matrix metalloproteinase activity significantly reduces NLRP3-mediated BBB impairment. Collectively, these findings reveal the important role of NLRP3-driven chemokine production in BBB disintegration, suggesting potential therapeutic targets to mitigate neuroinflammation. |
| format | Article |
| id | doaj-art-eaf355b038af498390ba8fad310cfad7 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-eaf355b038af498390ba8fad310cfad72025-01-19T12:29:57ZengNature PortfolioNature Communications2041-17232025-01-0116112110.1038/s41467-025-56097-1Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in miceSung-Hyun Yoon0Chae youn Kim1Eunju Lee2Changjun Lee3Kyung-Seo Lee4Jaeho Lee5Hana Park6Bokeum Choi7Inhwa Hwang8Junhan Kim9Tae-Gyun Kim10Junghyun Son11Young-Min Hyun12Seunghee Hong13Je-Wook Yu14Department of Microbiology and Immunology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of MedicineDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei UniversityDepartment of Microbiology and Immunology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of MedicineDepartment of Microbiology and Immunology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of MedicineDepartment of Microbiology and Immunology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of MedicineDepartment of Anatomy, Brain Korea 21 Project for Medical Science, Yonsei University College of MedicineDoping Control Center, Korea Institute of Science and TechnologyDepartment of Microbiology and Immunology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of MedicineDepartment of Microbiology and Immunology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of MedicineDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei UniversityDepartment of Dermatology, Yonsei University College of MedicineDoping Control Center, Korea Institute of Science and TechnologyDepartment of Anatomy, Brain Korea 21 Project for Medical Science, Yonsei University College of MedicineDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei UniversityDepartment of Microbiology and Immunology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of MedicineAbstract Blood-brain barrier (BBB) disintegration is a key contributor to neuroinflammation; however, the biological processes governing BBB permeability under physiological conditions remain unclear. Here, we investigate the role of NLRP3 inflammasome in BBB disruption following peripheral inflammatory challenges. Repeated intraperitoneal lipopolysaccharide administration causes NLRP3-dependent BBB permeabilization and myeloid cell infiltration into the brain. Using a mouse model with cell-specific hyperactivation of NLRP3, we identify microglial NLRP3 activation as essential for peripheral inflammation-induced BBB disruption. Conversely, NLRP3 and microglial gasdermin D (GSDMD) deficiency markedly attenuates lipopolysaccharide-induced BBB breakdown. Notably, IL-1β is not required for NLRP3-GSDMD-mediated BBB disruption. Instead, microglial NLRP3-GSDMD axis upregulates CXCL chemokines and matrix metalloproteinases around BBB via producing GDF-15, promoting the recruitment of CXCR2-containing neutrophils. Inhibition of neutrophil infiltration and matrix metalloproteinase activity significantly reduces NLRP3-mediated BBB impairment. Collectively, these findings reveal the important role of NLRP3-driven chemokine production in BBB disintegration, suggesting potential therapeutic targets to mitigate neuroinflammation.https://doi.org/10.1038/s41467-025-56097-1 |
| spellingShingle | Sung-Hyun Yoon Chae youn Kim Eunju Lee Changjun Lee Kyung-Seo Lee Jaeho Lee Hana Park Bokeum Choi Inhwa Hwang Junhan Kim Tae-Gyun Kim Junghyun Son Young-Min Hyun Seunghee Hong Je-Wook Yu Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice Nature Communications |
| title | Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice |
| title_full | Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice |
| title_fullStr | Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice |
| title_full_unstemmed | Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice |
| title_short | Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice |
| title_sort | microglial nlrp3 gasdermin d activation impairs blood brain barrier integrity through interleukin 1β independent neutrophil chemotaxis upon peripheral inflammation in mice |
| url | https://doi.org/10.1038/s41467-025-56097-1 |
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