Cerebral Pericytes and Endothelial Cells Communicate through Inflammasome-Dependent Signals

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.

A Quantum Dot Biomimetic for SARS-CoV-2 to Interrogate Dysregulation of the Neurovascular Unit Relevant to Brain Inflammation

“…3). The leakage across the monolayers and potential activation of proinflammatory signaling events was expected to induce neuroinflammation in the mixed neuroglial cultures (46)(47)(48). We fixed and stained the cultures with antibodies to microtubule associated protein 2 (MAP-2), postsynaptic density protein 95 (PSD-95), and glial fibrillary acidic protein (GFAP) to identify hallmarks of neuroinflammation such as dendritic beading, synaptic pruning, and astrogliosis, respectively (49)(50)(51)(52)(53).…”

Alterations of the blood-brain barrier during aging

“…Among these, matrix metalloprotease 9, chemokine CC chemokine ligand 2 (CCL2), and IL-6 are pro-inflammatory factors, whereas C-X3-C motif chemokine ligand 1 (CX3CL1) and IL-33 are anti-inflammatory factors. 35,36 During aging, more pro-inflammatory factors are secreted, leading to the breakdown of the basement membrane and endothelial tight junctions and the activation of astrocytes and microglia. 83 In addition to transmitting inflammatory factors, pericytes also participate in peripheral leukocyte invasion.…”

Cell non-autonomous regulation of cerebrovascular aging processes by the somatotropic axis

“…Tight junctions between endothelial cells are a main component of this barrier, leading to the requirement of facilitated transport for nutrient and waste exchange through the capillary endothelial cells. This highly regulated process allows the brain to be an immune-privileged organ giving the BBB an important role as a regulator of neuroinflammation and lymphocyte migration ( 237 , 242 – 244 ). Early evidence to support the idea of a multicellular barrier came from work showing that cultured astrocytes induced tighter junctions between endothelial cells ( 245 ).…”

“…Early evidence to support the idea of a multicellular barrier came from work showing that cultured astrocytes induced tighter junctions between endothelial cells ( 245 ). When degradation of the BBB begins (for example in inflammaging), small molecules such as cytokines can leak into the surrounding brain tissue leading to subsequent inflammation ( 19 , 243 , 244 , 246 ).…”