Integrin α9 on lymphatic endothelial cells regulates lymphocyte egress

Koyu Ito, Junko Morimoto, Akio Kihara, Yutaka Matsui, Daisuke Kurotaki, Masashi Kanayama, Szandor Simmons, Masaru Ishii, Dean Sheppard, Akinori Takaoka, Toshimitsu Uede

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3080-3085
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number8
DOIs
Publication statusPublished - 2014 Feb 25
Externally publishedYes

Keywords

  • Autoimmune disease
  • Lymphocyte trafficking
  • Matricellular proteins

ASJC Scopus subject areas

  • General

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