Integrin ?9 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, ?9 integrin, which is closely associated with activated ?1 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 ?9 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 ?9 integrin-dependent manner without affecting S1P synthesis and/or degradation. Blockade of ?9 integrin-mediated signaling reduced lymphocyte egress from dLNs in several models, including experimental autoimmune encephalomyelitis, where it improved clinical scores and pathology. Therefore, manipulating ?9 integrin function may offer a therapeutic strategy for treating various inflammatory disorders.

SUBMITTER: Ito K 

PROVIDER: S-EPMC3939877 | biostudies-other | 2014 Feb

REPOSITORIES: biostudies-other