Dataset Information

Cocaine-induced release of CXCL10 from pericytes regulates monocyte transmigration into the CNS.

ABSTRACT: Cocaine is known to facilitate the transmigration of inflammatory leukocytes into the brain, an important mechanism underlying neuroinflammation. Pericytes are well-recognized as important constituents of the blood-brain barrier (BBB), playing a key role in maintaining barrier integrity. In the present study, we demonstrate for the first time that exposure of human brain vascular pericytes to cocaine results in enhanced secretion of CXCL10, leading, in turn, to increased monocyte transmigration across the BBB both in vitro and in vivo. This process involved translocation of ?-1 receptor (?-1R) and interaction of ?-1R with c-Src kinase, leading to activation of the Src-PDGFR-?-NF-?B pathway. These findings imply a novel role for pericytes as a source of CXCL10 in the pericyte-monocyte cross talk in cocaine-mediated neuroinflammation, underpinning their role as active components of the innate immune responses.

SUBMITTER: Niu F

PROVIDER: S-EPMC6363463 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Cocaine-induced release of CXCL10 from pericytes regulates monocyte transmigration into the CNS.

Niu Fang F Liao Ke K Hu Guoku G Sil Susmita S Callen Shannon S Guo Ming-Lei ML Yang Lu L Buch Shilpa S

The Journal of cell biology 20190109 2

Cocaine is known to facilitate the transmigration of inflammatory leukocytes into the brain, an important mechanism underlying neuroinflammation. Pericytes are well-recognized as important constituents of the blood-brain barrier (BBB), playing a key role in maintaining barrier integrity. In the present study, we demonstrate for the first time that exposure of human brain vascular pericytes to cocaine results in enhanced secretion of CXCL10, leading, in turn, to increased monocyte transmigration ...[more]

PMID: 30626719

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Project description:We investigated the hypothesis that transmigration drives monocyte transcriptional changes. Using Agilent Whole Human Genome Microarrays, we identified over 600 differentially expressed genes (2x, p<0.05) in freshly isolated human monocytes following 1.5 h of transmigration across IL1beta-stimulated ECs compared to untreated monocytes. Genes up-regulated by monocyte transmigration belong to a number of overrepresented functional groups including immune response, and inhibition of apoptosis. qRT-PCR confirmed increased expression of monocyte chemotactic proteins 1 and 3 and of NLR family apoptosis inhibitory protein (NAIP) following monocyte transmigration. In addition, quantification of annexin V binding revealed a reduction in apoptosis following monocyte transmigration. Comparison of gene expression in transmigrated monocytes to additional controls (monocytes which failed to transmigrate and monocytes incubated beneath stimulated ECs) revealed 89 differentially expressed genes which were controlled by the physical process of diapedesis. Functional annotation of these genes showed down-regulation of antimicrobial genes (e.g. alpha-defensin down 50x, cathelicidin down 9x, and cathepsin G down 3x). qRT-PCR confirmed down-regulation of these genes. Immunoblots confirmed that monocyte transmigration down-regulates alpha-defensin protein expression. Overall, these data indicate that exposure of monocytes to stimulated ECs promotes further monocyte recruitment and inhibits monocyte apoptosis. Unexpectedly, following transmigration monocytes displayed reduced anti-microbial expression. Monocytes were allowed to transmigrate across IL1b stimulated HUVEC. Monocytes which transmigrated and monocytes which failed to transmigrate were collected after 1.5 hours from 3 experimental replicates of different human donors. Untreated monocytes were collected as a control from 4 human donors. Monocytes incubated beneath stimulated HUVEC for 1.5 hours were also collected from four human donors as a control.

Dataset Information

Cocaine-induced release of CXCL10 from pericytes regulates monocyte transmigration into the CNS.

Publications

Cocaine-induced release of CXCL10 from pericytes regulates monocyte transmigration into the CNS.

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