Knock-In Mice Expressing a 15-Lipoxygenating Alox5 Mutant Respond Differently to Experimental Inflammation Than Reported <i>Alox5<sup>−/−</sup></i> Mice
2021
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
Arachidonic acid 5-lipoxygenase (ALOX5) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes. We recently created knock-in mice (<i>Alox5</i>-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), <i>Alox5</i>-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), <i>Alox5</i>-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 (<i>Alox5</i><sup>−/−</sup> 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 <i>Alox5</i>-KI mice respond differently in two models of experimental inflammation than <i>Alox5<sup>−/−</sup></i> animals tested previously in similar experimental setups.
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