Activation of microglial NLRP3 inflammasome disrupts blood-brain barrier integrity through neutrophil chemotaxis during peripheral inflammation.
Recent research has shed light on the significant impact of the NLRP3 inflammasome, particularly its activation within microglia, on the integrity of the blood-brain barrier (BBB). This barrier, which protects the brain from inflammatory agents and toxins present in the bloodstream, becomes compromised during episodes of peripheral inflammation, leading to neuroinflammation and various neurological disorders.
Despite numerous studies linking systemic inflammation to neurodegeneration, the precise mechanisms governing BBB permeability remain largely unclear. Researchers at Yonsei University College of Medicine have made strides toward elucidation, highlighting the pivotal role of microglial NLRP3 activation following inflammatory challenges, such as the administration of lipopolysaccharides (LPS).
Using mouse models, the researchers conducted daily intraperitoneal LPS injections, simulating mild, repetitive peripheral inflammation. Their results indicated significant changes within the BBB, characterized by increased permeability and alteration of immune responses within the brain.
Notably, they found, "IL-1β is not required for NLRP3-GSDMD-mediated BBB disruption," indicating alternative pathways through which inflammation affects the BBB. This research posits both NLRP3 and gasdermin D (GSDMD) as key components driving these inflammatory responses.
The relationship between microglial activation and neutrophil recruitment is underscored by the findings, which demonstrate how the disruption of BBB integrity is enhanced by increased levels of chemokines produced following NLRP3 activation. "Collectively, these findings reveal the important role of NLRP3-driven chemokine production in BBB disintegration," the researchers stated.
With their results, scientists observed higher levels of matrix metalloproteinases (MMPs) as well, which play significant roles in cell migration and structural alterations to the BBB. They reported, "Neutrophil recruitment contributes to peripheral inflammation-induced BBB disruption," emphasizing the need for targeted therapeutic strategies.
Addressing the broader relevance of their work, the authors suggest potential pathways through which therapeutic interventions may help mitigate the effects of neuroinflammation on the BBB. Targeting the microglial NLRP3 signaling axis may represent groundbreaking approaches for treating neurological disorders linked to BBB dysfunction.
These findings pave the way for future studies aimed at leveraging this knowledge to develop new strategies for improving BBB integrity and combatting neuroinflammatory conditions more effectively.