Basophils balance healing after myocardial infarction via IL-4/IL-13
Florian Sicklinger, Ingmar Sören Meyer, Xue Li, Daniel Radtke, Severin Dicks, Moritz P. Kornadt, Christina Mertens, Julia K. Meier, Kory J. Lavine, Yunhang Zhang, Tim Christian Kuhn, Tobias Terzer, Jyoti Patel, Melanie Boerries, Gabriele Schramm, Norbert Frey, Hugo A. Katus, David Voehringer, Florian Leuschner
Florian Sicklinger, Ingmar Sören Meyer, Xue Li, Daniel Radtke, Severin Dicks, Moritz P. Kornadt, Christina Mertens, Julia K. Meier, Kory J. Lavine, Yunhang Zhang, Tim Christian Kuhn, Tobias Terzer, Jyoti Patel, Melanie Boerries, Gabriele Schramm, Norbert Frey, Hugo A. Katus, David Voehringer, Florian Leuschner
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Research Article Cardiology

Basophils balance healing after myocardial infarction via IL-4/IL-13

Abstract

The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6Clo macrophages toward increased numbers of inflammatory Ly6Chi monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of Ly6Chi monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/α-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels.

Authors

Florian Sicklinger, Ingmar Sören Meyer, Xue Li, Daniel Radtke, Severin Dicks, Moritz P. Kornadt, Christina Mertens, Julia K. Meier, Kory J. Lavine, Yunhang Zhang, Tim Christian Kuhn, Tobias Terzer, Jyoti Patel, Melanie Boerries, Gabriele Schramm, Norbert Frey, Hugo A. Katus, David Voehringer, Florian Leuschner

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Figure 5

Basophils contribute to IL-4 and IL-13 production in the injured heart after MI.

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Basophils contribute to IL-4 and IL-13 production in the injured heart a...
(A) mRNA expression of Il6, Tnfa, Il4, and Il13 in the infarct region 3 days after MI in WT and Baso-KO mice (n = 8–9). mRNA levels are expressed as x-fold relative to the WT MI group. Data show the mean ± SD. P values were determined by 2-way ANOVA followed by Sidak’s multiple-comparison test. (B) Representative flow cytometric plots of cells from the infarct region 3 days after MI in WT 4get and Baso-KO 4get mice. (C) Quantification of GFP+ cells in the infarct region 3 days after MI in control WT 4get and Baso-KO 4get mice (n = 5). Data show the mean ± SD. P value was determined by 2-tailed Student’s t test. (D) Gene expression dot plot based on single-cell RNA-Seq analysis of mouse cardiac leukocytes 3–7 days after MI. Mean expression is depicted by color intensity, whereas the dot size represents the fraction of cells expressing the indicated gene.