1. Macrophage-specific lipoxygenase deletion amplify cardiac repair activating Treg cells in chronic heart failure.
- Author
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Kain V, Grilo GA, Upadhyay G, Nadler JL, Serhan CN, and Halade GV
- Subjects
- Animals, Mice, Arachidonate 15-Lipoxygenase genetics, Arachidonate 15-Lipoxygenase deficiency, Arachidonate 15-Lipoxygenase metabolism, Mice, Inbred C57BL, Male, Myocardial Infarction immunology, Myocardial Infarction genetics, Myocardial Infarction pathology, Gene Deletion, Mice, Knockout, Arachidonate 12-Lipoxygenase genetics, Arachidonate 12-Lipoxygenase deficiency, Arachidonate 12-Lipoxygenase metabolism, Chronic Disease, Heart Failure immunology, Macrophages immunology, Macrophages metabolism, T-Lymphocytes, Regulatory immunology
- Abstract
Splenic leukocytes, particularly macrophage-expressed lipoxygenases, facilitate the biosynthesis of resolution mediators essential for cardiac repair. Next, we asked whether deletion of 12/15 lipoxygenase (12/15LOX) in macrophages impedes the resolution of inflammation following myocardial infarction (MI). Using 12/15flox/flox and LysMcre scheme, we generated macrophage-specific 12/15LOX (Mɸ-12/15LOX-/-) mice. Young C57BL/6J wild-type and Mɸ-12/15LOX-/- male mice were subjected to permanent coronary ligation microsurgery. Mice were monitored at day 1 (d1) to d5 (as acute heart failure [AHF]) and to d56 (chronic HF) post-MI, maintaining no MI as d0 naïve control animals. Post ligation, Mɸ-12/15LOX-/- mice showed increased survival (88% vs 56%) and limited heart dysfunction compared with wild-type. In AHF, Mɸ-12/15LOX-/- mice have increased biosynthesis of epoxyeicosatrienoic acid by 30%, with the decrease in D-series resolvins, protectin, and maresin by 70% in the infarcted heart. Overall, myeloid cell profiling from the heart and spleen indicated that Mɸ-12/15LOX-/- mice showed higher immune cells with reparative Ly6Clow macrophages during AHF. In addition, the detailed immune profiling revealed reparative macrophage phenotype (Ly6Clow) in Mɸ-12/15LOX-/- mice in a splenocardiac manner post-MI. Mɸ-12/15LOX-/- mice showed an increase in myeloid population that coordinated increase of T regulatory cells (CD4+/Foxp3+) in the spleen and injured heart at chronic HF compared with wild-type. Thus, macrophage-specific deletion of 12/15LOX directs reparative macrophage phenotype to facilitate cardiac repair. The presented study outlines the complex role of 12/15LOX in macrophage plasticity and T regulatory cell signaling that indicates that resolution mediators are viable targets to facilitate cardiac repair in HF post-MI., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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