Integrin α9 on lymphatic endothelial cells regulates lymphocyte egress

Sphingosine 1-phosphate (S1P) plays a role in lymphocyte egress from lymphoid organs. However, it remains unclear how S1P production and secretion are regulated. We show that under inflammatory conditions, α9 integrin, which is closely associated with activated β1 integrin, and its ligand, tenascin-...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-02, Vol.111 (8), p.3080-3085
Main Authors: Ito, Koyu, Morimoto, Junko, Kihara, Akio, Matsui, Yutaka, Kurotaki, Daisuke, Kanayama, Masashi, Simmons, Szandor, Ishii, Masaru, Sheppard, Dean, Takaoka, Akinori, Uede, Toshimitsu
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Encephalomyelitis, Autoimmune, Experimental - immunology
Endothelial cells
Endothelial Cells - metabolism
Flow Cytometry
Freund's Adjuvant
Histological Techniques
Immunologic Surveillance - immunology
Inflammation
Integrin alpha Chains - metabolism
Integrins
Ligands
Lymph nodes
Lymph Nodes - cytology
Lymphocytes
Lymphocytes - metabolism
Lysophospholipids - secretion
Macrophages
Mice
Mice, Inbred C57BL
Microscopy, Confocal
Secretion
Sinuses
Sphingosine - analogs & derivatives
Sphingosine - secretion
Statistics, Nonparametric
T lymphocytes
Tenascin - pharmacology
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Summary:Sphingosine 1-phosphate (S1P) plays a role in lymphocyte egress from lymphoid organs. However, it remains unclear how S1P production and secretion are regulated. We show that under inflammatory conditions, α9 integrin, which is closely associated with activated β1 integrin, and its ligand, tenascin-C, colocalize on medullary and cortical sinuses of draining lymph nodes (dLNs), which is a gate for lymphocyte exit, and that inhibition of lymphocyte egress is evident by blockade of α9 integrin-mediated signaling at dLNs. Based on in vitro analysis using lymphatic endothelial cells obtained from mice embryos, we suggested the possibility that stimulation of lymphatic endothelial cells by tenascin-C enhances S1P secretion in an α9 integrin-dependent manner without affecting S1P synthesis and/or degradation. Blockade of α9 integrin-mediated signaling reduced lymphocyte egress from dLNs in several models, including experimental autoimmune encephalomyelitis, where it improved clinical scores and pathology. Therefore, manipulating α9 integrin function may offer a therapeutic strategy for treating various inflammatory disorders.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1311022111