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CXCL10 promotes vascular permeability upon TNF-induced release from pericytes

ABSTRACT: Tumor necrosis factor alpha induces vascular permeability, playing an important role in inflammation. Also, TNF-induced vascular leakage is involved in the increased extravasation of nanoparticle formulated chemotherapeutics improving drug delivery and subsequently tumor response, and we found a positive correlation between the presence of pericytes in the tumor-associated vasculature and TNF-induced leakage. RNA sequencing and pathway analysis of TNF-stimulated versus non-stimulated pericytes and endothelial cells show significant upregulation of several pathways involving interferon regulating pathways with a high expression of CXCL10, also known as Interferon gamma-inducible protein 10 (IP-10) in TNF-stimulated pericytes. In addition, CXCL10 protein production was significantly increased in conditioned medium from TNF-exposed pericytes compared to the other conditions. In our animal studies, we observed that tumor types with high pericyte covered vessels show enhanced permeability when exposed to TNF, which can be blocked with a neutralizing CXCL10 antibody. Vice versa, tumors with vessels low in pericyte number do not respond to TNF, i.e., do not express elevated permeability. Importantly, this lack of pericyte coverage can be compensated by co-administration of CXCL10. Our finding reveals a mechanism where TNF induces CXCL10 release from pericytes, being at the basis of increased permeability and thus vascular leakage.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203505 | GEO | 2022/07/01

REPOSITORIES: GEO

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Project description:The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB. The brain microvascular fragments were isolated from mice with different genotypes, each represented by 3-4 biological replicates. Genotypes 1-2: Platelet derived growth factor-B (PDGF-B) retention-motif knockout (pdgfbret/ret) represent the pericyte-deficient situation, and the heterozygous mice (pdgfbret/+) are used as controls. Genotypes 3-4: Hypomorphic PDGF-B mutants that rescue pdgfb-/- null mice, in which a one copy of a conditionally silent human PDGF-B transgene targeted to the Rosa 26 locus (R26P) is turned on by endothelial-specific expression of Cre recombinase. In this data set these mice are named as Tie2Cre, R26P+/0, pdgfb-/- (representing the pericyte-deficient situation). Mice wt for pdgfb (pdgfb+/+) and carrying one silent copy of R26P (R26P+/0), are used as controls. Genotype 5: Adult Notch3+/+ wildtype (WT).

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CXCL10 promotes vascular permeability upon TNF-induced release from pericytes

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