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Effect of experimental stroke on meningeal gene expression and the influence of mast cells on these gene changes

ABSTRACT: Stroke is a leading cause of adult disability and death. Inflammation plays an important role in stroke pathology, but the factors which promote brain inflammation in this setting remain to be fully defined. Here we investigate the meninges, the membranes that envelop the brain, for a potential role in modulating immune cell trafficking to the brain. We also investigate the potential of mast cells (MCs) to modulate this response as MCs are often considered as 'first responders' playing a critical role in the initiation and development of inflammation in many disease settings. We find that stroke increases expression of inflammatory and immune response genes in the meninges in mice consistent with a potential role in modulating immune cell trafficking. Moreover, genetic and cell transfer approaches identify MCs as important modulators of this response.

ORGANISM(S): Mus musculus

PROVIDER: GSE51566 | GEO | 2014/07/31

SECONDARY ACCESSION(S): PRJNA223426

REPOSITORIES: GEO

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Project description:Background: Myeloid cells (MCs) reside in the aortic intima at regions predisposed to atherosclerosis. Systemic inflammation triggers reverse transendothelial migration (RTM) of intimal MCs into arterial blood, which orchestrates a protective immune response that clears intracellular pathogens from the arterial intima. Molecular pathways that regulate RTM remain poorly understood. Sphingosine-1-phosphate (S1P) is a lipid mediator that regulates immune cell trafficking by signaling via five G protein-coupled receptors (S1PRs). We investigated the role of S1P in the RTM of aortic intimal MCs. Methods: Intravenous injection of lipopolysaccharide (LPS) was used to model a systemic inflammatory stimulus that triggers RTM. CD11c+ intimal MCs in the lesser curvature of the ascending aortic arch were enumerated by en face confocal microscopy. Local gene expression was evaluated by transcriptomic analysis of microdissected intimal cells. Results: In wild-type C57BL/6 mice, LPS induced intimal cell expression of S1pr1, S1pr3, and sphingosine kinase 1 (Sphk1, a kinase responsible for S1P production). Pharmacological modulation of multiple S1PRs blocked LPS-induced RTM and modulation of S1PR1 and S1PR3 reduced RTM in an additive manner. Cre-mediated deletion of S1pr1 in MCs blocked LPS-induced RTM, confirming a role for myeloid-specific S1PR1 signaling. Global or hematopoietic deficiency of Sphk1 reduced plasma S1P levels, the abundance of CD11c+ MCs in the aortic intima and blunted LPS-induced RTM. In contrast, plasma S1P levels, the abundance of intimal MCs, and LPS-induced RTM were rescued in Sphk1-/- mice transplanted with Sphk1+/+ or mixed Sphk1 +/+ and -/- bone marrow. Stimulation with LPS increased endothelial permeability and intimal MC exposure to circulating factors such as S1P. Conclusions: Functional and expression studies support a novel role for S1P signaling in the regulation of LPS-induced RTM as well as the homeostatic maintenance of aortic intimal MCs. Our data provides insight into how circulating plasma mediators help orchestrate intimal MC dynamics.

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Effect of experimental stroke on meningeal gene expression and the influence of mast cells on these gene changes

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