Hypogelsolinemia is observed in patients with different states of acute or chronic
inflammation such as
sepsis,
rheumatoid arthritis, and
multiple sclerosis. In animal models of
sepsis, repletion of plasma
gelsolin reduces septic mortality. However, the functions of extracellular
gelsolin and the mechanisms leading to its protective nature are poorly understood. Potential mechanisms involve
gelsolin's extracellular actin scavenging function or its ability to bind bioactive
lipids or proinflammatory mediators, which would limit inflammatory responses and prevent tissue damage. Here we report that human plasma
gelsolin binds to
sphingosine 1-phosphate (S1P), a pleiotropic cellular agonist involved in various immune responses, and to its synthetic structural analog
FTY720P (
Gilenya). The fluorescence intensity of a
rhodamine B-labeled
phosphatidylinositol 4,5-bisphosphate binding
peptide derived from
gelsolin and the optical density of recombinant human plasma
gelsolin (rhpGSN) were found to decrease after the addition of S1P or
FTY720P.
Gelsolin's ability to depolymerize
F-actin also decreased progressively with increasing addition of S1P. Transient increases in phosphorylation of
extracellular signal-regulated kinase in bovine aortic endothelial cells (BAECs) after S1P treatment were inhibited by rhpGSN. The ability of S1P to increase
F-actin content and the elastic modulus of primary astrocytes and BAECs was also prevented by rhpGSN. Evaluation of S1P and
gelsolin levels in cerebrospinal fluid reveals a low concentration of
gelsolin and a high concentration of S1P in samples obtained from patients suffering from lymphatic
meningitis. These findings suggest that
gelsolin-mediated regulation of S1P bioactivity may be important to maintain immunomodulatory balance at inflammatory sites.