Circulating neutrophil anti-pathogen dysfunction in cirrhosis

Balazs, Irina; Stadlbauer, Vanessa

doi:10.1016/j.jhepr.2023.100871

Cited by 4 publications

(4 citation statements)

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“…Further consideration of the more unusual granulocyte populations (basophils and eosinophils) is also warranted based on our preliminary findings. Pro-inflammatory ‘low density’ neutrophils have been described in cirrhosis ( 50 ) and contribute to organ damage upon recruitment into tissue. These ‘primed’ cells are suggested by some to have impaired ROS production and compromised bacterial killing ability, although findings vary depending on the nature and severity of cirrhosis ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

“…Pro-inflammatory ‘low density’ neutrophils have been described in cirrhosis ( 50 ) and contribute to organ damage upon recruitment into tissue. These ‘primed’ cells are suggested by some to have impaired ROS production and compromised bacterial killing ability, although findings vary depending on the nature and severity of cirrhosis ( 50 ). Combined with reported deficiencies in neutrophil chemotaxis ( 51 ) and altered NET formation ( 52 ) in cirrhosis it is easy to appreciate how predisposition to bacterial infections may occur.…”

Section: Discussionmentioning

confidence: 99%

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Circulating myeloid populations have prognostic utility in alcohol-related liver disease

Khan,

Salman,

Harford

et al. 2024

Front. Immunol.

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IntroductionAlcohol-related liver disease (ARLD) accounts for over one third of all deaths from liver conditions, and mortality from alcohol-related liver disease has increased nearly five-fold over the last 30 years. Severe alcohol-related hepatitis almost always occurs in patients with a background of chronic liver disease with extensive fibrosis or cirrhosis, can precipitate ‘acute on chronic’ liver failure and has a high short-term mortality. Patients with alcohol-related liver disease have impaired immune responses, and increased susceptibility to infections, thus prompt diagnosis of infection and careful patient management is required. The identification of early and non-invasive diagnostic and prognostic biomarkers in ARLD remains an unresolved challenge. Easily calculated predictors of infection and mortality are required for use in patients who often exhibit variable symptoms and disease severity and may not always present in a specialized gastroenterology unit.MethodsWe have used a simple haematological analyser to rapidly measure circulating myeloid cell parameters across the ARLD spectrum.Results and DiscussionWe demonstrate for the first time that immature granulocyte (IG) counts correlate with markers of disease severity, and our data suggests that elevated counts are associated with increased short-term mortality and risk of infection. Other myeloid populations such as eosinophils and basophils also show promise. Thus IG count has the potential to serve alongside established markers such as neutrophil: lymphocyte ratio as a simply calculated predictor of mortality and risk of infectious complications in patients with alcohol-related hepatitis. This would allow identification of patients who may require more intensive management.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circulating myeloid populations have prognostic utility in alcohol-related liver disease

Khan,

Salman,

Harford

et al. 2024

Front. Immunol.

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“…Sarcopenia and liver cirrhosis are associated with chronic inflammation and alterations in the immune system ( Cruz-Jentoft and Sayer, 2019 ; Wang, 2022 ; Balazs and Stadlbauer, 2023 ); however, the role of NET formation in their pathogenesis is not well-described yet. Here, we aimed to study NET formation and other basic functions of neutrophils, such as phagocytosis and ROS production, in patients with sarcopenia, cirrhosis, and cirrhosis-associated sarcopenia.…”

Section: Discussionmentioning

confidence: 99%

“…Phagocytic capacity is usually found to be decreased and number of non-phagocytic cells increased in patients with liver cirrhosis. As for ROS production, the number of neutrophils with basal ROS production (or resting burst) and ROS production in response to fMLF (reflecting the number of primed neutrophils) was found to be elevated, and the number of neutrophils with ROS production in response to E. coli was found to be either decreased or unchanged in patients with liver cirrhosis compared to healthy controls ( Balazs and Stadlbauer, 2023 ). We did not find significant changes in either phagocytosis or ROS production of neutrophils in cirrhotic patients with or without sarcopenia in this study.…”

Section: Discussionmentioning

confidence: 99%

Primary sarcopenia is associated with elevated spontaneous NET formation

Balazs,

Stelzer,

Traub

et al. 2024

Front. Cell Dev. Biol.

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Introduction: Sarcopenia is a frequent complication of liver cirrhosis, but it can also occur independently as a result of any underlying cause. The immune system plays an important role in the pathogenesis of both liver cirrhosis and sarcopenia. Neutrophil function, including neutrophil extracellular trap (NET) formation, is linked to chronic inflammation; however, it has not been extensively studied in patients with sarcopenia. Here, we aim to study if main neutrophil functions, such as phagocytosis, reactive oxygen species (ROS) production, and NET formation, are altered in patients with sarcopenia with or without liver cirrhosis.Methods: Neutrophils from 92 patients (52 patients with liver cirrhosis and sarcopenia, 25 patients with liver cirrhosis without sarcopenia, and 15 patients with sarcopenia without liver cirrhosis) and 10 healthy controls were isolated and stimulated with heat-inactivated E. coli (250 bacteria/cell), phorbol 12-myristate 13-acetate (PMA) (100 nM), or incubation medium in duplicates for 2 h at 37°C. Cells were fixed with paraformaldehyde and stained with 4′,6-diamidino-2-phenylindole (DAPI). Pictures of 10 random fields of vision per slide were taken with an Olympus BX51 fluorescence microscope (Olympus, Shinjuku, Tokyo, Japan) at 600x total magnification. The DNA Area and NETosis Analysis (DANA) algorithm was used to quantify the percentage of NET formation per patient. Phagocytosis and ROS production were assessed with the PhagotestTM kit and PhagoburstTM kit (Glycotope, Heidelberg, Germany) in 92 patients and 21 healthy controls, respectively.Results: Spontaneous NET formation was significantly elevated in patients with only sarcopenia compared to patients with cirrhosis and sarcopenia (p = 0.008) and healthy controls (p = 0.039). NET formation in response to PMA was significantly decreased in patients with cirrhosis (p = 0.007), cirrhosis and sarcopenia (p < 0.001), and sarcopenia (p = 0.002) compared to healthy controls. There was no significant difference in NET formation in response to E. coli between the groups. The DANA algorithm was successfully optimized and validated for assessment of clinical samples. There were no significant changes in neutrophil phagocytosis between patients’ groups compared to healthy controls. A significantly lower percentage of neutrophils produced ROS in response to N-formylmethionine-leucyl-phenylalanine (fMLF) in patients compared to healthy controls.Discussion: Spontaneous NET formation might contribute to chronic inflammation and sarcopenia pathogenesis. This, however, does not result in the impairment of the NET formation function of neutrophils in response to a bacterial stimulus and, therefore, cannot be not linked with the increased risk of bacterial infections neither in sarcopenia nor in cirrhosis. The semi-automated NET formation analysis can be successfully implemented to analyze the vast amount of data generated within clinical studies. This approach opens up the possibilities to develop an NET formation-based biomarker in different diseases including sarcopenia and implement NET formation analysis into clinical settings. Phagocytosis and ROS production were not affected in patients with sarcopenia. Further research is needed to explore the mechanism of NET formation in patients with sarcopenia and its potential as a biomarker in sarcopenia.

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