title: Integrin α9 on lymphatic endothelial cells regulates lymphocyte egress.
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.
authors: Department of Matrix Medicine and Divisions of Molecular Immunology and Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo 060-0815, Japan.
authors: Koyu
authors: K
authors: Ito
authors: Junko
authors: J
authors: Morimoto
authors: Akio
authors: A
authors: Kihara
authors: Yutaka
authors: Y
authors: Matsui
authors: Daisuke
authors: D
authors: Kurotaki
authors: Masashi
authors: M
authors: Kanayama
authors: Szandor
authors: S
authors: Simmons
authors: Masaru
authors: M
authors: Ishii
authors: Dean
authors: D
authors: Sheppard
authors: Akinori
authors: A
authors: Takaoka
authors: Toshimitsu
authors: T
authors: Uede
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D005620:Freund's Adjuvant; D006652:Histological Techniques; D007157:Immunologic Surveillance / Q000276:immunology*; D039001:Integrin alpha Chains / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology; D008214:Lymphocytes / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D018709:Statistics, Nonparametric; D019063:Tenascin / Q000494:pharmacology
chemical_list: D039001:Integrin alpha Chains; D008246:Lysophospholipids; D019063:Tenascin; C084613:integrin alpha9; C060506:sphingosine 1-phosphate; D005620:Freund's Adjuvant; D013110:Sphingosine
keywords: autoimmune disease; lymphocyte trafficking; matricellular proteins