Plasma gelsolin modulates cellular response to sphingosine 1-phosphate

Area of Science:

• Biochemistry
• Immunology
• Cell Biology

Background:

• Hypogelsolinemia is linked to inflammatory conditions like sepsis and multiple sclerosis.
• Extracellular gelsolin's protective roles and mechanisms in inflammation are not fully understood.
• Potential functions include actin scavenging and binding inflammatory mediators.

Purpose of the Study:

• To investigate the interaction between human plasma gelsolin and sphingosine 1-phosphate (S1P).
• To elucidate gelsolin's role in regulating S1P's bioactivity in inflammatory contexts.

Main Methods:

• Assessed binding of S1P and FTY720P to gelsolin using fluorescence and optical density.
• Measured gelsolin's F-actin depolymerization activity in the presence of S1P.
• Investigated gelsolin's effect on S1P-induced signaling (ERK phosphorylation) and cellular changes (F-actin, elastic modulus) in endothelial cells and astrocytes.
• Analyzed gelsolin and S1P levels in cerebrospinal fluid from meningitis patients.

Main Results:

• Human plasma gelsolin binds to S1P and its analog FTY720P, reducing gelsolin's peptide binding and depolymerization activity.
• Gelsolin inhibited S1P-induced ERK phosphorylation and prevented S1P-mediated increases in F-actin content and cell stiffness.
• Cerebrospinal fluid from lymphatic meningitis patients showed low gelsolin and high S1P concentrations.

Conclusions:

• Gelsolin directly binds and modulates the bioactivity of S1P.
• This interaction impacts cellular responses to S1P, potentially limiting inflammation.
• Gelsolin-mediated regulation of S1P may be crucial for maintaining immunomodulatory balance at inflammatory sites.