Home Journals IL-33/ST2 pathway regulates neutrophil migration and predicts outcome in patients with severe alcoholic hepatitis✩

IL-33/ST2 pathway regulates neutrophil migration and predicts outcome in patients with severe alcoholic hepatitis✩

Credits to the Source Link Daniel
Large image of Fig. 6.

Alcoholic hepatitis is associated with a high incidence of infection, a major driver of short-term mortality. While several pathways have been investigated in decompensated cirrhosis9x[9]Gustot, T., Fernandez, J., Szabo, G., Albillos, A., Louvet, A., Jalan, R. et al. Sepsis in alcohol-related liver disease. J Hepatol. 2017;
67: 1031–1050
Abstract | Full Text | Full Text PDF | PubMed | Scopus (27)
| Google ScholarSee all References

Fig. 6

Main study findings.

The issue of controls is critical in translational research for alcoholic hepatitis. Indeed, most patients admitted with SAH (i.e. with a Maddrey discriminant function >32) have underlying cirrhosis. Thus, we used 2 different control groups (i.e. patients with cirrhosis and healthy controls) to prove that changes in the IL-33/ST2 pathway in SAH are related to alcoholic hepatitis rather than decompensated cirrhosis. Comparison between cirrhosis and controls also shows the defect in this pathway during liver decompensation without any inflammatory process.

Endotoxemia was quantified using the HPLC-MS/MS method to determine serum concentrations of 3-HM. We chose this technique because HPLC-MS/MS can more accurately identify patients with low-grade endotoxemia, compared to the classical LAL (limulus amebocyte lysate) test, due to its high specificity and low limits of detection and quantification. Moreover, the measurement is not affected by the lipid content of samples, thus avoiding bias due to lipid-rich particles observed with the LAL test.23x[23]Pais de Barros, J.-P., Gautier, T., Sali, W., Adrie, C., Choubley, H., Charron, E. et al. Quantitative lipopolysaccharide analysis using HPLC/MS/MS and its combination with the limulus amebocyte lysate assay. J Lipid Res. 2015;
56: 1363–1369
Crossref | PubMed | Scopus (33)
| Google ScholarSee all References

Herein, we confirm that patients with SAH have higher endotoxemia than patients with cirrhosis and controls.30x[30]Michelena, J., Altamirano, J., Abraldes, J.G., Affò, S., Morales-Ibanez, O., Sancho-Bru, P. et al. Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis. Hepatology. 2015;
62: 762–772
Crossref | PubMed | Scopus (112)
| Google ScholarSee all References

SIGIRR has been suggested to be a downregulator of the Toll-like receptor pathways implicated in sepsis in murine models, especially in neutrophils, with conflicting results in terms of functional consequences.31x[31]Ueno-Shuto, K., Kato, K., Tasaki, Y., Sato, M., Sato, K., Uchida, Y. et al. Lipopolysaccharide decreases single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR) expression by suppressing specificity protein 1 (Sp1) via the Toll-like receptor 4 (TLR4)-p38 pathway in monocytes and neutrophils. J Biol Chem. 2014;
289: 18097–18109
Crossref | PubMed | Scopus (21)
| Google ScholarSee all References

Because the incidence of infection is a major driver of mortality in SAH,5x[5]Thursz, M.R., Richardson, P., Allison, M., Austin, A., Bowers, M., Day, C.P. et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;
372: 1619–1628
Crossref | PubMed | Scopus (255)
| Google ScholarSee all References

There has been no significant improvement in the pharmaceutical management of SAH in the past few years. Based on the knowledge that infection is associated with a high short-term probability of death, results in trials testing antibiotic prophylaxis are expected (Rifaximin: NCT02116556; Ciprofloxacin: NCT02326103; Amoxicillin and Clavulanate: NCT02281929). While strategies with antibiotics are promising, they do not restore the immune defect associated with SAH. Stimulating PMN migration to the site of infection with IL-33 might represent an appealing option. Indeed, alterations in migration capacity have been associated with an increased risk of infection in humans.40x[40]Egger, G., Aigner, R., Glasner, A., Hofer, H.P., Mitterhammer, H., and Zelzer, S. Blood polymorphonuclear leukocyte migration as a predictive marker for infections in severe trauma: comparison with various inflammation parameters. Intensive Care Med. 2004;
30: 331–334
Crossref | PubMed | Scopus (29)
| Google ScholarSee all References

While neutrophils were treated with a dose of 50 ng/ml in the ex vivo experiments, the detected dose in the serum was around 100 pg/ml. Such a difference can be viewed as a supraphysiological stimulus. Other authors have also used similar doses.20x[20]Alves-Filho, J.C., Sônego, F., Souto, F.O., Freitas, A., Verri, W.A., Auxiliadora-Martins, M. et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat Med. 2010;
16: 708–712
Crossref | PubMed | Scopus (289)
| Google ScholarSee all References

In the present study, the IL-33/ST2 pathway did not modulate the phagocytic capacity of circulating PMNs suggesting that this pathway only improves PMNs influx at the site of infection. We would like to underline that impairment in neutrophil function during ALD is not restricted to decreased phagocytosis but also includes defects in microbial killing with several pathways involved such as myeloperoxidase, TIM-3, PD-1, etc.9x[9]Gustot, T., Fernandez, J., Szabo, G., Albillos, A., Louvet, A., Jalan, R. et al. Sepsis in alcohol-related liver disease. J Hepatol. 2017;
67: 1031–1050
Abstract | Full Text | Full Text PDF | PubMed | Scopus (27)
| Google ScholarSee all References

Alcoholic hepatitis is a complex disease and the role of PMNs is not fully understood. Indeed, there is a paradox between the liver infiltration by neutrophils (suggesting that activation of these cells is harmful to the liver) and a defect in neutrophil migration capacity (suggesting that a defect in PMN function is harmful to infection). In addition, IL-8 is the most upregulated cytokine in patients with acute drinking/alcoholic hepatitis vs. patients without SAH in the CANONIC study evaluating the profile of patients with acute-on-chronic liver failure.45x[45]Clària, J., Stauber, R.E., Coenraad, M.J., Moreau, R., Jalan, R., Pavesi, M. et al. Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure. Hepatology. 2016;
64: 1249–1264
Crossref | PubMed | Scopus (173)
| Google ScholarSee all References

In conclusion, this study shows that circulating neutrophil migration is altered in SAH and that this defect is reversible by restoring the IL-33/ST2 pathway. Circulating sST2 levels are associated with survival and the probability of infection. Our results suggest that treatment with IL-33 represents a new potential therapeutic strategy to decrease the risk of infection in SAH.

Abbreviations

3-HM, 3-hydroxymyristate; ALD, alcohol-related liver disease; AH, alcoholic hepatitis; Cirrh, cirrhosis; Ctrls, controls; DAMP, damage-associated molecular pattern; HR, hazard ratio; IFN, interferon; LPS, lipopolysaccharide; MELD, model for end-stage liver disease; MFI, mean fluorescent intensity; MIRU, mean intensity with relative units; PMN, polymorphonuclear neutrophils; SAH, severe alcoholic hepatitis; sST2, soluble ST2.

Source Link

Related Articles

Leave a Comment

This website uses cookies to improve your experience. We will assume you are ok with this, but you can opt-out if you wish. Accept Read More

%d bloggers like this: