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Inflammatory monocyte-derived S1P in the lymph node regulates immune response

ABSTRACT: Sphingosine 1-phosphate (S1P), a lipid chemoattractant, guides immune cells from the low-S1P environment of tissues into the high-S1P environment of circulatory fluids. Most notably, S1P directs T cell exit from lymph nodes (LN), where T cells are initially activated to fight pathogens, into lymph, from which T cells flow into blood and ultimately reach inflamed tissues. T cells follow these gradients primarily using S1P receptor 1 (S1PR1). The drugs Gilenya and Siponimod, both FDA-approved for the autoimmune disease multiple sclerosis, target S1PR1. They blind self-reactive T cells to S1P gradients, block them from exiting LN, and thus prevent them from infiltrating the central nervous system. While recent work has revealed key aspects of how S1P gradients are established at steady-state, very little is known about S1P distribution in disease, and in turn how changing S1P gradients may affect the immune response. Here, we find that LN S1P increases during an immune response, which prolongs the time T cells spend in the LN before exiting into lymph. Inflammatory monocytes, which had not previously been implicated in shaping S1P gradients, are an important source of this S1P. Inflammatory monocytes must express the early activation marker CD69 to supply S1P to T cells; CD69 represses transcription of S1P receptor 5 (S1pr5), enabling monocytes to infiltrate the LN T zone and efficiently release S1P. Here we compared RNA sequencing of inflammatory monocytes WT or CD69-KO infiltrating the draining lymph node.$

ORGANISM(S): Mus musculus

PROVIDER: GSE139006 | GEO | 2020/12/23

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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Inflammatory monocyte-derived S1P in the lymph node regulates immune response

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