Granzymes A and B Regulate the Local Inflammatory Response during &lt;b&gt;&lt;i&gt;Klebsiella pneumoniae&lt;/i&gt;&lt;/b&gt; Pneumonia

García‐Laorden, M. Isabel; Stroo, Ingrid; Blok, Dana C.; Florquin, Sandrine; Medema, Jan Paul; Vos, Alex F. de; Poll, Tom van der

doi:10.1159/000443401

Cited by 30 publications

(31 citation statements)

References 29 publications

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“…As expected [23], NK cells were the main cell type expressing gzms. The percentage of NK cells in PLF-expressing gzmA decreased over time; a similar pattern was seen for gzmB, albeit to a lesser extent and after an initial not significant increase.…”

Section: Discussionsupporting

confidence: 86%

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

García‐Laorden

Stroo

Terpstra

et al. 2017

Mediators of Inflammation

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Escherichia (E.) coli is the most common causative pathogen in peritonitis, the second most common cause of sepsis. Granzymes (gzms) are serine proteases traditionally implicated in cytotoxicity and, more recently, in the inflammatory response. We here sought to investigate the role of gzms in the host response to E. coli-induced peritonitis and sepsis in vivo. For this purpose, we used a murine model of E. coli intraperitoneal infection, resembling the clinical condition commonly associated with septic peritonitis by this bacterium, in wild-type and gzmA-deficient (gzmA−/−), gzmB−/−, and gzmAxB−/−mice. GzmA and gzmB were predominantly expressed by natural killer cells, and during abdominal sepsis, the percentage of these cells expressing gzms in peritoneal lavage fluid decreased, while the amount of expression in the gzm+ cells increased. Deficiency of gzmA and/or gzmB was associated with increased bacterial loads, especially in the case of gzmB at the primary site of infection at late stage sepsis. While gzm deficiency did not impact neutrophil recruitment into the abdominal cavity, it was accompanied by enhanced nucleosome release at the primary site of infection, earlier hepatic necrosis, and more renal dysfunction. These results suggest that gzms influence bacterial growth and the host inflammatory response during abdominal sepsis caused by E. coli.

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Section: Discussionsupporting

confidence: 86%

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

García‐Laorden

Stroo

Terpstra

et al. 2017

Mediators of Inflammation

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“…Mice lacking Gzms exhibited a reduced immune tolerance and increased inflammation levels through a type I interferon-dependent pathway, leading to the development of autoimmune diseases, including diabetes (43,45) and ulcerative colitis (46). These two autoimmune diseases were further associated with SNHL (47,48).…”

Section: Discussionmentioning

confidence: 99%

Screening of genes associated with inﬂammatory responses in the endolymphatic sac reveals underlying mechanisms for autoimmune inner ear diseases

Zhang

Wang

2018

Exp Ther Med

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The current study analyzed gene expression profiles of the endolymphatic sac (ES) in rats and identified expressed genes, present in the human and rat ES, to reveal key hubs for inflammatory responses. Microarray data (accession no. E-MEXP-3022) were obtained from the European Bioinformatics Institute database, including three biological replicates of ES plus dura tissues and three replicates of pure dura tissues form rats. Differentially expressed genes (DEGs) were screened using the Linear Model for Microarray data method and a protein-protein interaction (PPI) network was constructed using data from the Search Tool for the Retrieval of Interacting Genes/Proteins database followed by a module analysis via Clustering with Overlapping Neighborhood Expansion. Function enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery online tool. A total of 612 DEGs were identified, including 396 upregulated and 216 downregulated genes. Gene ontology term enrichment analysis indicated DEGs were associated with cell adhesion, including α5-integrin (Itga1) and secreted phosphoprotein 1 (Spp1); T cell co-stimulation, including C-C chemokine ligand (Ccl)21 and Ccl19; and the toll-like receptor signaling pathway, including toll-like receptor (Tlr)2, Tlr7 and Tlr8. These conclusions were supported by Kyoto Encyclopedia of Genes and Genomes pathway analyses revealing extracellular matrix-receptor interaction, including Itga1 and Spp1; leukocyte transendothelial migration, includingclaudin-4 (Cldn4); and malaria, including Tlr2. The hub roles of Itga1, Cd24 and Spp1 were revealed by calculating three topological properties of the PPI network. Ccl21, Ccl19 and Cldn4 were demonstrated to be crucial following significant module analysis according to the corresponding threshold, which revealed they were enriched in inflammation pathways. Tlr7, Tlr2, granzyme m and Tlr8 were common genes associated with inflammatory responses in rat and human ES. In conclusion, abnormal expression of the aforementioned inflammation-associated genes may be associated with the development of autoimmune inner ear diseases.

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“…GzmA Ϫ/Ϫ mice were more susceptible to ectromelia infection (1,22) and the parasite Trypanosoma cruzi (12, 23) than WT mice. However, GzmA did not seem to play an important role during infection with either lymphocytic choriomeningitis virus or Listeria monocytogenes (6) or K. pneumoniae (9) and GzmA Ϫ/Ϫ mice were protected from death during influenza infection (2). GzmA Ϫ/Ϫ mice were resistant to endotoxic shock, illustrating the proinflammatory properties of this protease (21).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, whole blood stimulation with Gram-negative and Gram-positive bacteria resulted in GzmA release by leukocytes (13). In contrast, GzmA did not seem to play an important role during infection with lymphocytic choriomeningitis virus, Listeria monocytogenes (6), or Klebsiella (K.) pneumoniae (9) and was reported to contribute to lethality during influenza (2) and endotoxic shock (21).…”

Section: Streptococcus (S)mentioning

confidence: 99%

Granzyme A impairs host defense duringStreptococcus pneumoniaepneumonia

Boogaard

Gisbergen

Vernooy

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia (CAP). Granzyme A (GzmA) is a serine protease produced by a variety of cell types involved in the immune response. We sought to determine the role of GzmA on the host response during pneumococcal pneumonia. GzmA was measured in bronchoalveolar lavage fluid (BALF) harvested from CAP patients from the infected and contralateral uninfected side and in lung tissue slides from CAP patients and controls. In CAP patients, GzmA levels were increased in BALF obtained from the infected lung. Human lungs showed constitutive GzmA expression by both parenchymal and nonparenchymal cells. In an experimental setting, pneumonia was induced in wild-type (WT) and GzmA-deficient (GzmA−/−) mice by intranasal inoculation of S. pneumoniae. In separate experiments, WT and GzmA−/− mice were treated with natural killer (NK) cell depleting antibodies. Upon infection with S. pneumoniae, GzmA−/− mice showed a better survival and lower bacterial counts in BALF and distant body sites compared with WT mice. Although NK cells showed strong GzmA expression, NK cell depletion did not influence bacterial loads in either WT or GzmA−/− mice. These results implicate that GzmA plays an unfavorable role in host defense during pneumococcal pneumonia by a mechanism that does not depend on NK cells.

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Granzymes A and B Regulate the Local Inflammatory Response during <b><i>Klebsiella pneumoniae</i></b> Pneumonia

Cited by 30 publications

References 29 publications

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

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

Screening of genes associated with inﬂammatory responses in the endolymphatic sac reveals underlying mechanisms for autoimmune inner ear diseases

Granzyme A impairs host defense duringStreptococcus pneumoniaepneumonia

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