Cerebral Pericytes and Endothelial Cells Communicate through Inflammasome-Dependent Signals.

Mihály Kozma,Attila E Farkas,Ádám Nyúl-Tóth,Ádám Mészáros,Imola Wilhelm,Csilla Fazakas,István A Krizbai,Zsófia Hernádi,Kinga Molnár,Laura Costea

doi:10.3390/ijms22116122

Abstract

By upregulation of cell adhesion molecules and secretion of proinflammatory cytokines, cells of the neurovascular unit, including pericytes and endothelial cells, actively participate in neuroinflammatory reactions. As previously shown, both cell types can activate inflammasomes, cerebral endothelial cells (CECs) through the canonical pathway, while pericytes only through the noncanonical pathway. Using complex in vitro models, we demonstrate here that the noncanonical inflammasome pathway can be induced in CECs as well, leading to a further increase in the secretion of active interleukin-1β over that observed in response to activation of the canonical pathway. In parallel, a more pronounced disruption of tight junctions takes place. We also show that CECs respond to inflammatory stimuli coming from both the apical/blood and the basolateral/brain directions. As a result, CECs can detect factors secreted by pericytes in which the noncanonical inflammasome pathway is activated and respond with inflammatory activation and impairment of the barrier properties. In addition, upon sensing inflammatory signals, CECs release inflammatory factors toward both the blood and the brain sides. Consequently, CECs activate pericytes by upregulating their expression of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), an inflammasome-forming pattern recognition receptor. In conclusion, cerebral pericytes and endothelial cells mutually activate each other in inflammation.

Highlights

We have previously shown that cerebral endothelial cells (CECs) can activate inflammasomes through the canonical pathway [17], whereas the canonical inflammasome activation pathway was found to be inactive in brain pericytes
We aimed to understand whether the noncanonical pathway could be induced in CECs beside canonical inflammasome activation that we reported previously
All of these results show that CECs detect factors secreted by pericytes in which the noncanonical inflammasome pathway is activated and respond with inflam

Summary

Introduction

An increasing body of evidence suggests that vascular cells, namely cerebral endothelial cells (CECs) and pericytes, participate in and modulate inflammatory reactions of the central nervous system (CNS). Endothelial activation and dysfunction are key elements of neuroinflammation in several cerebral pathologies, including neurodegeneration, infection, stroke, and aging [1]. Inflammatory responses of the neurovascular unit (NVU) can be among the first alterations in several cerebral pathologies. Vascular dysfunction may precede cognitive decline and neurodegenerative changes in Alzheimer’s disease (AD), whereas cerebral amyloid angiopathy is one of the hallmarks of the disease [2]. Increased permeability of the blood–brain barrier (BBB), enhanced expression of endothelial adhesion molecules, and consequent diapedesis of different leukocyte subsets complete the picture in both AD [3] and other neuroinflammatory conditions such as stroke [4] or infections [5]

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