Knock-In Mice Expressing a 15-Lipoxygenating Alox5 Mutant Respond Differently to Experimental Inflammation Than Reported <i>Alox5<sup>−/−</sup></i> Mice
Eugenia Marbach-Breitrück,
Nadine Rohwer,
Carmen Infante-Duarte,
Silvina Romero-Suarez,
Dominika Labuz,
Halina Machelska,
Laura Kutzner,
Nils Helge Schebb,
Michael Rothe,
Pallu Reddanna,
Karsten H. Weylandt,
Lothar H. Wieler,
Dagmar Heydeck,
Hartmut Kuhn
Affiliations
Eugenia Marbach-Breitrück
Department of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Chariteplatz 1, 10117 Berlin, Germany
Nadine Rohwer
Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, Ruppin General Hospital, Brandenburg Medical School, Fehrbelliner Straße 38, 16816 Neuruppin, Germany
Carmen Infante-Duarte
Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Silvina Romero-Suarez
Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Dominika Labuz
Department of Experimental Anesthesiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
Halina Machelska
Department of Experimental Anesthesiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
Laura Kutzner
Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaussstraße 20, 42119 Wuppertal, Germany
Nils Helge Schebb
Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaussstraße 20, 42119 Wuppertal, Germany
Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, Andhra Pradesh, India
Karsten H. Weylandt
Division of Medicine, Department of Gastroenterology, Metabolism and Oncology, Ruppin General Hospital, Brandenburg Medical School, Fehrbelliner Straße 38, 16816 Neuruppin, Germany
Lothar H. Wieler
Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany
Dagmar Heydeck
Department of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Chariteplatz 1, 10117 Berlin, Germany
Hartmut Kuhn
Department of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Chariteplatz 1, 10117 Berlin, Germany
Arachidonic acid 5-lipoxygenase (ALOX5) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes. We recently created knock-in mice (Alox5-KI) which express an arachidonic acid 15-lipoxygenating Alox5 mutant instead of the 5-lipoxygenating wildtype enzyme. These mice were leukotriene deficient but exhibited an elevated linoleic acid oxygenase activity. Here we characterized the polyenoic fatty acid metabolism of these mice in more detail and tested the animals in three different experimental inflammation models. In experimental autoimmune encephalomyelitis (EAE), Alox5-KI mice displayed an earlier disease onset and a significantly higher cumulative incidence rate than wildtype controls but the clinical score kinetics were not significantly different. In dextran sodium sulfate-induced colitis (DSS) and in the chronic constriction nerve injury model (CCI), Alox5-KI mice performed like wildtype controls with similar genetic background. These results were somewhat surprising since in previous loss-of-function studies targeting leukotriene biosynthesis (Alox5−/− mice, inhibitor studies), more severe inflammatory symptoms were observed in the EAE model but the degree of inflammation in DSS colitis was attenuated. Taken together, our data indicate that these mutant Alox5-KI mice respond differently in two models of experimental inflammation than Alox5−/− animals tested previously in similar experimental setups.
