antibodies toward SHARPIN
(red) and caspase 1 (green).
Cell on right showing increase
in caspase 1 upon stimulation
with LPS and ATP and co-
localization with SHARPIN as
visualized by the merged
fluorescence (yellow). Nuclei
are stained blue with DAPI.
Image courtesy of The
American Journal of Pathology
A new study suggests that SHARPIN, a protein involved in regulating inflammation, has anti-septic effects.
Researchers believe this discovery, reported in The American Journal of Pathology, could spur the development of novel treatments for sepsis.
“Sepsis has been linked to enhanced activity of the enzyme caspase 1 and aberrant expression of pro-inflammatory interleukins 1β and 18,” said Liliana Schaefer, MD, of Goethe-Universität in Frankfurt, Germany.
“SHARPIN binds to caspase 1 and inhibits its activation. Our study proposes that the caspase 1/SHARPIN interaction may be a key pharmacological target in sepsis and perhaps in other inflammatory conditions where SHARPIN is involved.”
The researchers found that sepsis in mice bred to be deficient in SHARPIN resulted in enhanced levels of interleukins 1β and 18 and active caspase 1, as well as shortened survival.
Treatment with a caspase 1 inhibitor reversed these effects—reducing levels of interleukins 1β and 18, decreasing cell death in the spleen, and prolonging survival.
The researchers also found evidence to suggest this mechanism may be relevant to human sepsis.
“We found a decline in SHARPIN levels in septic patients correlating with enhanced activation of caspase 1 in circulating mononuclear cells and an increase of interleukin 1β/18 in the plasma,” Dr Schaefer said.
“Our findings suggest that using pharmacological caspase 1 inhibitors could be beneficial in septic patients with low SHARPIN levels, and these therapies may be more efficient than other anti-inflammatory therapies.”
