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Cited by 109Sphingolipid Metabolism and SignalingLymphatic System and DiseasesLysosomal Storage Disorders Research

Vascular and immunobiology of the circulatory sphingosine 1-phosphate gradient

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Yanagida, Keisuke, Hla, Timothy·2017·Annual Review of Physiology
DOI 10.1146/annurev-physiol-021014-071635PMC PMC5500220
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Abstract

Vertebrates are endowed with a closed circulatory system, the evolution of which required novel structural and regulatory changes. Furthermore, immune cell trafficking paradigms adapted to the barriers imposed by the closed circulatory system. How did such changes occur mechanistically? We propose that spatial compartmentalization of the lipid mediator sphingosine 1-phosphate (S1P) may be one such mechanism. In vertebrates, S1P is spatially compartmentalized in the blood and lymphatic circulation, thus comprising a sharp S1P gradient across the endothelial barrier. Circulatory S1P has critical roles in maturation and homeostasis of the vascular system as well as in immune cell trafficking. Physiological functions of S1P are tightly linked to shear stress, the key biophysical stimulus from blood flow. Thus, circulatory S1P confinement could be a primordial strategy of vertebrates in the development of a closed circulatory system. This review discusses the cellular and molecular basis of the S1P gradients and aims to interpret its physiological significance as a key feature of the closed circulatory system.

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  • S1P is the primary chemoattractant that drives the exit of activated and recirculating lymphocytes from lymph nodes into efferent LVs.

    “S1P is the primary chemoattractant that drives the exit of activated and recirculating lymphocytes from lymph nodes into efferent LVs (106, 122, 123).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [123]

    The section “Trafficking of Immune Cells at the Tissue-Circulatory Interface” (page unavailable) says lymphocytes exit lymphoid organs into blood or lymph by sensing S1P gradients, and that depleting circulating S1P severely inhibits egress. It does not specify activated and recirculating lymphocytes, identify efferent lymphatic vessels as the route, or establish S1P as the primary chemoattractant relative to others. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Lymphocytes residing in the lymph node parenchyma express high levels of S1PR1 that they use to sense the S1P gradient, resulting in lymph node egress.

    “Lymphocytes that reside in the lymph node parenchyma express high levels of S1PR1 that they use to sense the S1P gradient, resulting in lymph node egress (106, 123).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [123]

    The “Trafficking of Immune Cells at the Tissue-Circulatory Interface” section says lymphocytes sense S1P gradients through S1P1 at egress portals, supporting the egress mechanism. It does not establish that lymphocytes in the lymph node parenchyma express high levels of S1P1; the discussion of receptor internalization concerns circulating lymphocytes. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Higher levels of S1P in lymph and blood cause downregulation and desensitization of S1PR1 on lymphocytes, facilitating their entry into lymph nodes from afferent LVs and blood against S1P gradients.

    “In contrast, the higher levels of S1P in lymph and blood cause downregulation and desensitization of S1PR1 on lymphocytes that facilitate their entry into lymph nodes from afferent LVs and blood against S1P gradients (106, 123).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [123]

    The ‘Trafficking of Immune Cells at the Tissue-Circulatory Interface’ section says high circulating S1P internalizes and desensitizes lymphocyte S1P1, allowing lymphocytes to overcome attraction to blood and return to lymphoid tissues; it also describes impaired lymph-node entry when this regulation is disrupted. The ‘S1P in Lymph Circulation’ section links lymph S1P exposure to reduced surface S1P1, but our copy does not specifically establish entry into lymph nodes from afferent lymphatic vessels by this mechanism. Page numbers are unavailable in the indexed passages. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • S1P is present in much higher concentrations in lymph and blood than in the lymph node parenchyma.

    “Synthesized by endothelial cells, S1P is present in much higher concentrations in lymph and blood than in the lymph node parenchyma (106, 123).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [123]

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Cited by

Sorted by citations

Authors
Yanagida, K., & Hla, T.
Affiliations
Boston Children's Hospital (US)
ORCID
Hla, Timothy
Venue
Annual Review of Physiology
Publisher
Annual Reviews
Published
2017-02-10
Volume
79
Issue
1
Pages
67-91
ISSN
  • 0066-4278 (ISSN-L)
  • 1545-1585
DOI
10.1146/annurev-physiol-021014-071635
PMC
PMC5500220
OpenAlex
W2461079494
Cited by
109
References
3
Citations by year
2026: 7 · 2025: 4 · 2024: 9 · 2023: 9 · 2022: 16 · 2021: 13 · 2020: 18 · 2019: 16 · 2018: 8 · 2017: 9
FWCI
1.00
Type
journal article
Language
en
Open access
Locations
  • Annual Review of Physiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Fondation Leducq
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL067330, R37HL067330, R01HL089934, U54HL117798)
  • National Cancer Institute (P01CA077839)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
sphingosine-1-phosphate, closed circulatory system, immune cell trafficking, endothelial barrier, shear stress, vascular development, lymphatic circulation, lipid mediators, vascular homeostasis
MeSH terms
Animals, Cardiovascular System, Homeostasis, Humans, Lysophospholipids, Sphingosine

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