Interleukin-11 plays a key role in human and mouse alcohol-related liver disease

Effenberger, M.; Grabherr, F.; Schaefer, B.; Grander, C.; Mayr, L.; Schwaerzler, J.; Enrich, B.; Moser, P.; Fink, J.; Pedrini, A.; Jaschke, N.; Freund, M.; Loizides, A.; Bale, R.; Putzer, D.; Widjaja, A. A.; Schaefer, S.; Cook, S.; Zoller, H.; Oberhuber, G.; Adolph, T. E.; Tilg, H.

doi:10.1101/2021.08.24.456749

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bioRxiv · 10.1101/2021.08.24.456749

Interleukin-11 plays a key role in human and mouse alcohol-related liver disease

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Abstract

BackgroundAlcoholic hepatitis (AH) reflects acute exacerbation of alcoholic liver disease (ALD) and is a growing healthcare burden worldwide with limited treatment options. Interleukin-11 (IL-11) is a pro-fibrotic, pro-inflammatory cytokine with increasingly recognized toxicities in parenchymal and epithelial cells. AimThe aim of this study was to explore the prognostic value of IL-11 serum levels in patients suffering from AH and cirrhosis of various etiology and to understand the role of IL-11 in experimental ALD. MethodsIL-11 serum concentration and tissue expression was determined in a cohort comprising 50 patients with AH, 110 patients with cirrhosis and 19 healthy volunteers. Findings were replicated in an independent patient cohort including 186 patients. Ethanol-fed wildtype mice were treated with a neutralizing murine IL-11 receptor-antibody (anit-IL11RA) and thereafter examined for severity signs and markers of ALD. ResultsHuman IL-11 serum concentration and liver tissue expression increased with severity of liver disease and were most pronounced in AH. In a multivariate Cox-regression, a serum level above 6.4 picograms/milliliter was a MELD independent risk factor for transplant-free liver disease survival in patients with compensated and decompensated cirrhosis. Findings were confirmed in an independent cohort. In mice, severity of alcohol-induced liver inflammation was positively correlated to enhanced hepatic IL-11 expression. Pretreatment with a neutralizing anti-IL11RA inhibited hepatic inflammation and mice were protected from ethanol-induced liver injury. In comparison to IgG-control, ethanol-fed mice treated with anti-IL11RA showed decreased steatosis, hepatic neutrophil infiltration, and expression of pro-inflammatory cytokines. ConclusionIL-11 plays a crucial role in the pathogenesis of ALD and could serve as an independent prognostic factor for transplant-free survival. Blocking IL-11 signaling might be a therapeutic option in human ALD, particularly AH.

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Effenberger, M., Grabherr, F., Schaefer, B., Grander, C., Mayr, L., Schwaerzler, J., Enrich, B., Moser, P., Fink, J., Pedrini, A., Jaschke, N., Freund, M., Loizides, A., Bale, R., Putzer, D., Widjaja, A. A., Schaefer, S., Cook, S., Zoller, H., Oberhuber, G., Adolph, T. E., Tilg, H.. 2021-08-25. Interleukin-11 plays a key role in human and mouse alcohol-related liver disease. https://doi.org/10.1101/2021.08.24.456749

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