Pericytes Regulate Vascular Basement Membrane Remodeling and Govern Neutrophil Extravasation during Inflammation

Abstract

During inflammation polymorphonuclear neutrophils (PMNs) traverse venular walls, composed of the endothelium, pericyte sheath and vascular basement membrane. Compared to PMN transendothelial migration, little is known about how PMNs penetrate the latter barriers. Using mouse models and intravital microscopy, we show that migrating PMNs expand and use the low expression regions (LERs) of matrix proteins in the vascular basement membrane (BM) for their transmigration. Importantly, we demonstrate that this remodeling of LERs is accompanied by the opening of gaps between pericytes, a response that depends on PMN engagement with pericytes. Exploring how PMNs modulate pericyte behavior, we discovered that direct PMN-pericyte contacts induce relaxation rather than contraction of pericyte cytoskeletons, an unexpected response that is mediated by inhibition of the RhoA/ROCK signaling pathway in pericytes. Taking our in vitro results back into mouse models, we present evidence that pericyte relaxation contributes to the opening of the gaps between pericytes and to the enlargement of the LERs in the vascular BM, facilitating PMN extravasation. Our study demonstrates that pericytes can regulate PMN extravasation by controlling the size of pericyte gaps and thickness of LERs in venular walls. This raises the possibility that pericytes may be targeted in therapies aimed at regulating inflammation.

Lipopolysaccharide Activates Toll-like Receptor 4 (TLR4)-mediated NF-κB Signaling Pathway and Proinflammatory Response in Human Pericytes

“…But LPS-treated pericytes not only produce chemokines that could attract immune cells, they also overexpress adhesion molecules such as ICAM-1 and VCAM-1. Recent works have demonstrated that mouse pericytes facilitate neutrophil transmigration through postcapillary venular walls in an ICAM-1-dependent manner using a model of TNF-␣-or IL-1␤-stimulated mouse muscle in vivo (51,52). In fact, capillary and arteriolar NG2 ϩ pericytes can "instruct" extravasating neutrophils and monocytes with migratory cues (53).…”

α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation

“…As described previously (42), retroviral packing was performed using a combination of human 293FT cells, the packing plasmids, and the pGFP-C-shLenti-vector carrying scrambled or rat α-syn-specific shRNA (Origene Technologies). Infection of rat neuron-enriched cultures was performed overnight by adding the media collected from the transfected 293FT cell cultures to each neuron-enriched culture, along with 6 μg/mL polybrene.…”

Pericytes in Vascular Development and Function

“…Transmigration of neutrophils into the surrounding tissue takes place through venules at permissive sites that lack mural cell coverage and have different basement membrane components [125][126][127][128]. Real-time imaging to monitor neutrophil transmigration in living inflamed tissue has demonstrated that, after transendothelial migration, neutrophils crawl along pericytes, which are mediated via intercellular adhesion molecule-1 (ICAM1)-Macrophage-1 antigen (Mac1) interaction [127].…”

“…Mural cells also react to inflammatory stimuli (e.g. tumor necrosis factor) by the expansion of pericyte gaps, thus enabling neutrophil to exit these structures [127,128]. Interestingly, the expansion of gaps between pericytes was induced by neutrophil-pericyte interaction that supressed actomyosin-based contractility in pericytes [128].…”