Novel Research Lays the Groundwork for New Therapies Against Sepsis

Protective role for SHARPIN, a protein involved in regulating inflammation, according to report in The American Journal of Pathology

Philadelphia, PA, April 8, 2016

Sepsis represents a serious complication of infection and is one of the leading causes of death and critical illness worldwide due in part to the lack of effective therapies. A report in The American Journal of Pathology provides evidence from both mouse and human studies that SHARPIN, a protein involved in regulating inflammation, has anti-septic effects. These findings may spur development of novel sepsis treatments.

“Sepsis has been linked to enhanced activity of the enzyme caspase 1 and aberrant expression of pro-inflammatory interleukins 1β and 18. 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,” explained Liliana Schaefer, MD, Professor of Pharmacology at the Institut fur Allgemeine Pharmakologie und Toxikologie of the Klinikum der Goethe-Universität Frankfurt am Main (Germany).

The investigators 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 by reducing levels of interleukins 1β and 18, decreasing cell death in the spleen, and prolonging survival.

The investigators also reported for the first time that 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 interleukin1β/18 in the plasma,” noted Dr. Schaefer. “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.”

Confocal images of human monocytes immunostained with antibodies toward SHARPIN (red) and caspase 1 (green).

Confocal images of human monocytes immunostained with antibodies toward SHARPIN (red) and caspase 1 (green). Notice the dramatic increase in caspase 1 upon stimulation with lipopolysaccharide (LPS) and ATP, and its co-localization with SHARPIN as visualized by the merged fluorescence (yellow). Nuclei are stained blue with DAPI.

A recent Task Force convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (JAMA 2016;315:801) define sepsis as “a life-threatening organ dysfunction caused by a dysregulated host response to infection.” Septic shock comprises a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are severe enough to substantially increase the risk of death. Symptoms of sepsis include changes in body temperature, rapid heart rate, and rapid breathing. Other indicators are reduced urine output, changes in mental status, breathing difficulty, abdominal pain, and low platelet count.

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Notes for editors
“An Essential Role for SHARPIN in the Regulation of Caspase 1 Activity in Sepsis,” by Madalina-Viviana Nastase, Jinyang Zeng-Brouwers, Helena Frey, Louise Tzung-Harn Hsieh, Chiara Poluzzi, Janet Beckmann, Nina Schroeder, Josef Pfeilschifter, Jaime Lopez-Mosqueda, Jan Mersmann, Fumiyo Ikeda, Renato V. Iozzo, Ivan Dikic, and Liliana Schaefer (DOI: http://dx.doi.org/10.1016/j.ajpath.2015.12.026). This article appears online ahead of The American Journal of Pathology, Volume 186, Issue 5 (May 2016) published by Elsevier.

Full text of this study is available to credentialed journalists upon request; contact Eileen Leahy at +1 732-238-3628 or ajpmedia@elsevier.com. Journalists wishing to interview the authors should contact Ricarda Wessinghage at +49 69 / 6301-6444 or Ricarda.Wessinghage@kgu.de.

This research was supported by the German Research Council (SCHA 1082/6-1, SFB 815, project A5 (Liliana Schaefer), A7 (Josef Pfeilschifter), and A17 (Jan Mersmann), SFB 1039, project B2 (Liliana Schaefer), LOEWE program Ub-Net (Liliana Schaefer and Madalina-Viviana Nastase).

About The American Journal of Pathology
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – close to 40,000 cites in 2014 – with an Impact Factor of 4.591 and Eigenfactor of 0.06689 according to the 2014 Journal Citation Reports®, Thomson Reuters, 2015, and an h-index of 217 according to the 2014 SCImago Journal and Country Rank.

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