Regulation of BzATP-Induced Blood–Brain Barrier Endothelial Cell Hyperpermeability by NLRP3 Inflammasome Inhibition

IF 1.9 4区医学 Q3 HEMATOLOGY Microcirculation Pub Date : 2025-03-07 DOI:10.1111/micc.70006

Aliyah Anderson, O'lisa Yaa Waithe, Gabriela Seplovich, Oluwatoyin Olagunju, Christlyn Greene, Amrendra Singh, Saravanakumar Muthusamy, Binu Tharakan

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Abstract

Objective

The blood–brain barrier (BBB) is a semi-permeable microvascular barrier, composed of endothelial cells conjoined by tight junction proteins. Following pathological conditions, i.e., traumatic brain injury (TBI), BBB dysfunction occurs, leading to microvascular hyperpermeability, resulting in cerebral edema formation and elevated intracranial pressure. Recent evidence suggests that the activation of pro-inflammatory signaling pathways is critical to BBB dysfunction. The NLRP3 inflammasome has been implicated as a key component of pro-inflammatory signaling. The aim of this study was to determine the upstream regulators of NLRP3 inflammasome activation that cause subsequent BBB aberration and microvascular hyperpermeability.

Methods

Brain microvascular endothelial cells were exposed to benzoyl ATP (BzATP) with or without MCC950. We employed immunocytochemical localization of tight junction proteins, fluorometric enzymatic assays, total gene expression analyses of ZO-1, and monolayer permeability studies to assess the effect of BzATP-induced injury on NLRP3 inflammasome activation/inhibition.

Results

BzATP treatment induced monolayer hyperpermeability and increased caspase-1 and MMP-9 activities. NLRP3 inhibition decreased caspase-1 and MMP-9 activities and rescued BzATP-induced monolayer permeability significantly.

Conclusions

NLRP3 inflammasome signaling is critical to BBB endothelial cell dysfunction. Extracellular ATP is an upstream promoter of BBB hyperpermeability. NLRP3 inflammasome activation leads to subsequent caspase-1 and MMP-9-mediated tight junction protein disarray.

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来源期刊

Microcirculation 医学-外周血管病

CiteScore

5.00

自引率

4.20%

发文量

审稿时长

6-12 weeks

期刊介绍： The journal features original contributions that are the result of investigations contributing significant new information relating to the vascular and lymphatic microcirculation addressed at the intact animal, organ, cellular, or molecular level. Papers describe applications of the methods of physiology, biophysics, bioengineering, genetics, cell biology, biochemistry, and molecular biology to problems in microcirculation. Microcirculation also publishes state-of-the-art reviews that address frontier areas or new advances in technology in the fields of microcirculatory disease and function. Specific areas of interest include: Angiogenesis, growth and remodeling; Transport and exchange of gasses and solutes; Rheology and biorheology; Endothelial cell biology and metabolism; Interactions between endothelium, smooth muscle, parenchymal cells, leukocytes and platelets; Regulation of vasomotor tone; and Microvascular structures, imaging and morphometry. Papers also describe innovations in experimental techniques and instrumentation for studying all aspects of microcirculatory structure and function.