Basophils balance healing after myocardial infarction via IL-4/IL-13
Florian Sicklinger, … , David Voehringer, Florian Leuschner
Florian Sicklinger, … , David Voehringer, Florian Leuschner
Published July 1, 2021
Citation Information: J Clin Invest. 2021;131(13):e136778. https://doi.org/10.1172/JCI136778.
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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 2

Basophil depletion by antibody injection worsens cardiac function after acute MI in mice.

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Basophil depletion by antibody injection worsens cardiac function after ...
(A) Timeline of basophil depletion experiments. (B) Frequencies of basophils from of hearts of IgG-injected control and anti-FcεRI–injected animals were assessed by flow cytometry 2 days (d2) after MI (n = 4). Data show the mean ± SD. P value was determined by 2-tailed Student’s t test. (C) Echocardiographic evaluation of baseline EF in IgG- and MAR-1–treated mice. (D) Plasma levels of cTnT in IgG- and MAR-1–treated mice were measured 24 hours after LAD ligation or sham intervention. P values were determined by 2-way ANOVA followed by Tukey’s multiple-comparison test. (E–H) Echocardiographic results for IgG-treated and MAR-1–treated mice 4 weeks after MI or sham surgery. P values were determined by 2-way ANOVA followed by Tukey’s multiple-comparison test. (I) Representative echocardiographic images 4 weeks after MI. Vectors display the direction and magnitude of myocardial contraction at midsystole. (J) Quantification of heart weight to body weight ratio (HW/BW) determined 4 weeks after MI (n = 4–8). Data show the mean ± SD. P values were determined by 2-way ANOVA followed by Tukey’s multiple-comparison test. (K) Representative hearts from IgG- and MAR-1–treated mice 4 weeks after MI or sham intervention. Arrowheads indicate the site of ligation. Scale bars: 500 μm.