2. Academic Validation
  3. Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice

Microglial NLRP3-gasdermin D activation impairs blood-brain barrier integrity through interleukin-1β-independent neutrophil chemotaxis upon peripheral inflammation in mice

  • Nat Commun. 2025 Jan 15;16(1):699. doi: 10.1038/s41467-025-56097-1.
Sung-Hyun Yoon # 1,  Chae Youn Kim # 2,  Eunju Lee 1 3,  Changjun Lee 1,  Kyung-Seo Lee 1,  Jaeho Lee 4,  Hana Park 5,  Bokeum Choi 1,  Inhwa Hwang 1,  Junhan Kim 2,  Tae-Gyun Kim 6,  Junghyun Son 5,  Young-Min Hyun 4,  Seunghee Hong 7,  Je-Wook Yu 8
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 2 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
  • 3 Division of Developmental Biology, National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD, USA.
  • 4 Department of Anatomy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 5 Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
  • 6 Department of Dermatology, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 7 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. seungheehong@yonsei.ac.kr.
  • 8 Department of Microbiology and Immunology, Brain Korea 21 Project for Medical Science, Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea. jewookyu@yuhs.ac.
  • # Contributed equally.
PMID: 39814731 DOI: 10.1038/s41467-025-56097-1
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.

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