Alox12/15 deficiency exacerbates, while Lipoxin A4 ameliorates hepatic inflammation in murine alcoholic hepatitis

  • Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A4 (LXA4), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA4 on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15+/+ and Alox12/15−/− mice, with or without supplementation of LXA4. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA4 significantly lowered transaminase levels only in Alox12/15−/− mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA4 injection attenuated selected parameters of disease progression in Alox12/15−/− mice, its beneficial impact on immunity was also apparent in Alox12/15+/+ mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.

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Author:Alexander David Roger QueckORCiDGND, Annika F. FinkGND, Evelyn Nicole Joy Sirait-FischerORCiDGND, Sabrina Rüschenbaum, Dominique Jeanette ThomasORCiDGND, Ryan G. SnodgrassORCiD, Gerd GeisslingerORCiDGND, Hideo Andreas Baba, Jonel TrebickaORCiDGND, Stefan ZeuzemORCiDGND, Andreas WeigertORCiDGND, Christian LangeGND, Bernhard BrüneORCiD
Parent Title (English):Frontiers in immunology
Place of publication:Lausanne
Document Type:Article
Date of Publication (online):2020/07/14
Date of first Publication:2020/07/14
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/08/25
Tag:alcoholic hepatitis; arachidonate 12/15-lipoxygenase (Alox12/15); lipoxin A4; resolution of inflammation; specialized pro-resolving lipid mediators (SPMs)
Issue:art. 1447
Page Number:13
First Page:1
Last Page:13
© 2020 Queck, Fink, Sirait-Fischer, Rüschenbaum, Thomas, Snodgrass, Geisslinger, Baba, Trebicka, Zeuzem, Weigert, Lange and Brüne. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0