Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models
Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in the pathogenesis of inflammatory diseases, and its pro- and anti-inflammatory effects have been reported for different ALOX-isoforms. Human ALOX15B oxygenates arachidonic acid to its 15-hydroperoxy derivative, whereas the corre...
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| author | Marjann Schäfer Florian Reisch Dominika Labuz Halina Machelska Sabine Stehling Gerhard P. Püschel Michael Rothe Dagmar Heydeck Hartmut Kuhn |
| author_facet | Marjann Schäfer Florian Reisch Dominika Labuz Halina Machelska Sabine Stehling Gerhard P. Püschel Michael Rothe Dagmar Heydeck Hartmut Kuhn |
| author_sort | Marjann Schäfer |
| collection | DOAJ |
| description | Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in the pathogenesis of inflammatory diseases, and its pro- and anti-inflammatory effects have been reported for different ALOX-isoforms. Human ALOX15B oxygenates arachidonic acid to its 15-hydroperoxy derivative, whereas the corresponding 8-hydroperoxide is formed by mouse Alox15b (Alox8). This functional difference impacts the biosynthetic capacity of the two enzymes for creating pro- and anti-inflammatory eicosanoids. To explore the functional consequences of the humanization of the reaction specificity of mouse <i>Alox15b</i> in vivo, we tested <i>Alox15b</i> knock-in mice that express the arachidonic acid 15-lipoxygenating Tyr603Asp and His604Val double mutant of <i>Alox15b</i>, instead of the arachidonic acid 8-lipoxygenating wildtype enzyme, in two different animal inflammation models. In the dextran sodium sulfate-induced colitis model, female <i>Alox15b</i>-KI mice lost significantly more bodyweight during the acute phase of inflammation and recovered less rapidly during the resolution phase. Although we observed significant differences in the colonic levels of selected pro- and anti-inflammatory eicosanoids during the time-course of inflammation, there were no differences between the two genotypes at any time-point of the disease. In Freund’s complete adjuvant-induced paw edema model, <i>Alox15b</i>-KI mice were less susceptible than outbred wildtype controls, though we did not observe significant differences in pain perception (Hargreaves-test, von Frey-test) when the two genotypes were compared. our data indicate that humanization of the reaction specificity of mouse <i>Alox15b</i> (<i>Alox8</i>) sensitizes mice for dextran sodium sulfate-induced experimental colitis, but partly protects the animals in the complete Freund’s adjuvant-induced paw edema model. |
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| language | English |
| last_indexed | 2024-03-11T01:38:18Z |
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| spelling | doaj.art-9dea358c140149189ab9d2eb5e3daf462023-11-18T16:47:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124131103410.3390/ijms241311034Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation ModelsMarjann Schäfer0Florian Reisch1Dominika Labuz2Halina Machelska3Sabine Stehling4Gerhard P. Püschel5Michael Rothe6Dagmar Heydeck7Hartmut Kuhn8Department of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, GermanyDepartment of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, GermanyDepartment of Experimental Anesthesiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, D-12203 Berlin, GermanyDepartment of Experimental Anesthesiology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, D-12203 Berlin, GermanyDepartment of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, GermanyInstitute for Nutritional Sciences, University Potsdam, Arthur-Scheunert-Allee 114–116, D-14558 Nuthetal, GermanyLipidomix GmbH, Robert-Roessle-Straße 10, D-13125 Berlin, GermanyDepartment of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, GermanyDepartment of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, GermanyMammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in the pathogenesis of inflammatory diseases, and its pro- and anti-inflammatory effects have been reported for different ALOX-isoforms. Human ALOX15B oxygenates arachidonic acid to its 15-hydroperoxy derivative, whereas the corresponding 8-hydroperoxide is formed by mouse Alox15b (Alox8). This functional difference impacts the biosynthetic capacity of the two enzymes for creating pro- and anti-inflammatory eicosanoids. To explore the functional consequences of the humanization of the reaction specificity of mouse <i>Alox15b</i> in vivo, we tested <i>Alox15b</i> knock-in mice that express the arachidonic acid 15-lipoxygenating Tyr603Asp and His604Val double mutant of <i>Alox15b</i>, instead of the arachidonic acid 8-lipoxygenating wildtype enzyme, in two different animal inflammation models. In the dextran sodium sulfate-induced colitis model, female <i>Alox15b</i>-KI mice lost significantly more bodyweight during the acute phase of inflammation and recovered less rapidly during the resolution phase. Although we observed significant differences in the colonic levels of selected pro- and anti-inflammatory eicosanoids during the time-course of inflammation, there were no differences between the two genotypes at any time-point of the disease. In Freund’s complete adjuvant-induced paw edema model, <i>Alox15b</i>-KI mice were less susceptible than outbred wildtype controls, though we did not observe significant differences in pain perception (Hargreaves-test, von Frey-test) when the two genotypes were compared. our data indicate that humanization of the reaction specificity of mouse <i>Alox15b</i> (<i>Alox8</i>) sensitizes mice for dextran sodium sulfate-induced experimental colitis, but partly protects the animals in the complete Freund’s adjuvant-induced paw edema model.https://www.mdpi.com/1422-0067/24/13/11034eicosanoidslipidsmetabolismfatty acidsinflammationatherosclerosis |
| spellingShingle | Marjann Schäfer Florian Reisch Dominika Labuz Halina Machelska Sabine Stehling Gerhard P. Püschel Michael Rothe Dagmar Heydeck Hartmut Kuhn Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models International Journal of Molecular Sciences eicosanoids lipids metabolism fatty acids inflammation atherosclerosis |
| title | Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models |
| title_full | Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models |
| title_fullStr | Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models |
| title_full_unstemmed | Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models |
| title_short | Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models |
| title_sort | humanization of the reaction specificity of mouse alox15b inversely modified the susceptibility of corresponding knock in mice in two different animal inflammation models |
| topic | eicosanoids lipids metabolism fatty acids inflammation atherosclerosis |
| url | https://www.mdpi.com/1422-0067/24/13/11034 |
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