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Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis. | LitMetric

AI Article Synopsis

  • - Peritonitis can lead to sepsis, a severe inflammatory condition, and this study investigates the role of Granzyme A (GzmA), a protein produced by immune cells, in this process and its potential as a therapeutic target.
  • - The research involved analyzing GzmA levels in patients with peritonitis and using mice models to study the effects of GzmA deficiency and inhibition on survival and inflammation during sepsis.
  • - The results showed that higher GzmA levels are linked to worse outcomes in patients and that inhibiting GzmA in mice led to improved survival rates, suggesting GzmA contributes to inflammatory responses but does not affect bacterial control.

Article Abstract

Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis. The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times. Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα. Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914344PMC
http://dx.doi.org/10.7150/thno.49288DOI Listing

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