RRC ID 29217
Author Ito K, Morimoto J, Kihara A, Matsui Y, Kurotaki D, Kanayama M, Simmons S, Ishii M, Sheppard D, Takaoka A, Uede T.
Title Integrin α9 on lymphatic endothelial cells regulates lymphocyte egress.
Journal Proc Natl Acad Sci U S A
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.
Volume 111(8)
Pages 3080-5
Published 2014-2-25
DOI 10.1073/pnas.1311022111
PII 1311022111
PMID 24516133
PMC PMC3939877
MeSH Animals Encephalomyelitis, Autoimmune, Experimental / immunology* Endothelial Cells / metabolism* Flow Cytometry Freund's Adjuvant Histological Techniques Immunologic Surveillance / immunology* Integrin alpha Chains / metabolism* Lymph Nodes / cytology Lymphocytes / metabolism Lysophospholipids / metabolism* Mice Mice, Inbred C57BL Microscopy, Confocal Sphingosine / analogs & derivatives* Sphingosine / metabolism Statistics, Nonparametric Tenascin / pharmacology
IF 9.412
Times Cited 14
Mice RBRC00169