Expression and Function of Granzymes A and B in<i>Escherichia coli</i>Peritonitis and Sepsis

García‐Laorden, M. Isabel; Stroo, Ingrid; Terpstra, Sanne; Florquin, Sandrine; Medema, Jan Paul; Veer, Cornelis van ’t; Vos, Alex F. de; Poll, Tom van der

doi:10.1155/2017/4137563

Cited by 22 publications

(20 citation statements)

References 30 publications

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“…In addition, CLP sepsis shows a high degree of similarity with the progression of human sepsis, displaying both the hyper- and hypo-inflammatory responses characteristic of human sepsis 32 , 33 . It has been shown previously that GzmA might contribute to septic shock induced by LPS 16 , 17 or to sepsis induced by single bacterial agents like the mouse pathogen B. microti 18 , S. pneumoniae 19 or E. coli 34 . However, the role of GzmA in abdominal polymicrobial sepsis had so far not been explored.…”

Section: Discussionmentioning

confidence: 99%

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Garzón-Tituaña¹,

Sierra-Monzón²,

Comas³

et al. 2021

Theranostics

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Aims: 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. Methods: 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. Results: 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 in vitro, 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. Conclusions: 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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Section: Discussionmentioning

confidence: 99%

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Garzón-Tituaña¹,

Sierra-Monzón²,

Comas³

et al. 2021

Theranostics

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“…This is a new finding, which somewhat contradicts the known increased tumor/nontumor ratios for total amount of the two SFs [1] , [8] , [11] , [13] . Although Mw-shifted-HNRNPA1 or -SRSF1 inducing clinical status has rarely been studied, a granzyme (cytotoxic protease upregulated during bacterial infection and released by immune cells)-treated cell line model showed cleavage of HNRNPA1 as a mobility shift (faster migration) on an immunoblot, which is fairly consistent with the relative levels of LMw-HNRNPA1 in PNPE and TBPE [6] , [30] ; these types of PEs are associated with bacterial infection and immune cell activation [21] , [23] , [24] , [25] , [26] .…”

Section: Discussionmentioning

confidence: 67%

Expression Profile of Three Splicing Factors in Pleural Cells Based on the Underlying Etiology and Its Clinical Values in Patients with Pleural Effusion

Han

Kim

Choi

et al. 2018

Translational Oncology

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Splicing factors (SFs) are involved in oncogenesis or immune modulation, the common underlying processes giving rise to pleural effusion (PE). The expression profiles of three SFs (HNRNPA1, SRSF1, and SRSF3) and their clinical values have never been assessed in PE. The three SFs (in pellets of PE) and conventional tumor markers were analyzed using PE samples in patients with PE (N = 336). The sum of higher–molecular weight (Mw) forms of HNRNPA1 (Sum-HMws-HNRNPA1) and SRSF1 (Sum-HMws-SRSF1) and SRSF3 levels were upregulated in malignant PE (MPE) compared to benign PE (BPE); they were highest in cytology-positive MPE, followed by tuberculous PE and parapneumonic PE. Meanwhile, the lowest-Mw HNRNPA1 (LMw-HNRNPA1) and SRSF1 (LMw-SRSF1) levels were not upregulated in MPE. Sum-HMws-HNRNPA1, Sum-HMws-SRSF1, and SRSF3, but neither LMw-HNRNPA1 nor LMw-SRSF1, showed positive correlations with cancer cell percentages in MPE. The detection accuracy for MPE was high in the order of carcinoembryonic antigen (CEA, 85%), Sum-HMws-HNRNPA1 (76%), Sum-HMws-SRSF1 (68%), SRSF3, cytokeratin-19 fragments (CYFRA 21-1), LMw-HNRNPA1, and LMw-SRSF1. Sum-HMws-HNRNPA1 detected more than half of the MPE cases that were undetected by cytology and CEA. Sum-HMws-HNRNPA1, but not other SFs or conventional tumor markers, showed an association with longer overall survival among patients with MPE receiving chemotherapy. Our results demonstrated different levels of the three SFs with their Mw-specific profiles depending on the etiology of PE. We suggest that Sum-HMws-HNRNPA1 is a supplementary diagnostic marker for MPE and a favorable prognostic indicator for patients with MPE receiving chemotherapy.

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“…The activity of Gzms during infectious diseases and sepsis seems to differ between anatomical site as well as the type of pathogen involved. For instance, a study showed that there was low level of GzmA in peritoneal lavage fluid of healthy mice while this level increased overtime during sepsis induced by E. coli (43). On the other hand, in a pneumonia-induced sepsis using a gram positive bacteria (Streptococcus pneumoniae) model the opposite was found (42).…”

Section: Granzymes Are Elevated In Patients Suffering From Sepsismentioning

confidence: 99%

The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover

et al. 2020

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Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem.

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Expression and Function of Granzymes A and B inEscherichia coliPeritonitis and Sepsis

Cited by 22 publications

References 30 publications

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Expression Profile of Three Splicing Factors in Pleural Cells Based on the Underlying Etiology and Its Clinical Values in Patients with Pleural Effusion

The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover

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