Endothelial signaling loop plays role in cytokine storm
MedWire News: US researchers have identified an endothelial signaling loop important in the initiation of the cytokine amplification during influenza virus infection.
"S1P1 receptor signaling in the endothelium provides a mechanism for the attenuation of influenza virus-induced morbidity and reveals an unexpected role for endothelial cells as regulators of cytokine storm," report Hugh Rosen (Scripps Research Institute, La Jolla, California) and colleagues in the journal Cell.
Cytokine storm, or immunologic storm, is a reaction that results in cytokines and chemokines infiltrating the tissues and blood, resulting in an inflammatory response. Macrophages and other immune cells flood the lungs, also, and this can cause fatal lung damage.
In the present study, Rosen and colleagues used various chemical and genetic analyses to investigate processes underlying this phenomenon. They tracked the role of the sphingosine-1-phosphate (S1P) receptor, S1P1, which is expressed on endothelial cells and lymphocytes in lung tissue.
Manipulating the S1P1 receptors in the endothelial cells in lung tissue significantly affected cytokine release, suppressing cytokine and innate immune cell recruitment in wild-type and lymphocyte-deficient mice.
In another experiment, the group assessed the effect of blocking the S1P1 receptor with a selective molecule in mice infected with a human pandemic influenza strain. In doing so, the immune reaction was downregulated, and cytokine storm diminished, and eliminated in some mice, which resulted in improved survival.
These findings suggest that endothelial cells are "central regulators of cytokine storm," say the researchers.
The group also observed immune cell infiltration and cytokine production were distinct events orchestrated by endothelial cells. These findings show, for the first time, that the adverse effects of cytokine storm differed from viral replication and pathologic changes in infected cells, they note.
Cytokine secretion and immune cell infiltration are separate events, both of which are regulated by the pulmonary endothelium, they add.
"The findings provide a new paradigm for understanding influenza and could point the way to new therapies," Rosen commented, in a press statement.
Future studies on the S1P1 receptor will aim to determine the individuals most susceptible to cytokine storm, and who would benefit most from drug therapy, says the team.
By MedWire Reporters