IL-13 promotes functional recovery after myocardial infarction via direct signaling to macrophages
Santiago Alvarez-Argote, Samantha J. Paddock, Michael A. Flinn, Caelan W. Moreno, Makenna C. Knas, Victor A. Almeida, Sydney L. Buday, Amirala Bakhshian Nik, Michaela Patterson, Yi-Guang Chen, Chien-Wei Lin, Caitlin C. O’Meara
Santiago Alvarez-Argote, Samantha J. Paddock, Michael A. Flinn, Caelan W. Moreno, Makenna C. Knas, Victor A. Almeida, Sydney L. Buday, Amirala Bakhshian Nik, Michaela Patterson, Yi-Guang Chen, Chien-Wei Lin, Caitlin C. O’Meara
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Research Article Cardiology

IL-13 promotes functional recovery after myocardial infarction via direct signaling to macrophages

Abstract

There is great interest in identifying signaling pathways that promote cardiac repair after myocardial infarction (MI). Prior studies suggest a beneficial role for IL-13 signaling in neonatal heart regeneration; however, the cell types mediating cardiac regeneration and the extent of IL-13 signaling in the adult heart after injury are unknown. We identified an abundant source of IL-13 and the related cytokine, IL-4, in neonatal cardiac type 2 innate lymphoid cells, but this phenomenon declined precipitously in adult hearts. Moreover, IL-13 receptor deletion in macrophages impaired cardiac function and resulted in larger scars early after neonatal MI. By using a combination of recombinant IL-13 administration and cell-specific IL-13 receptor genetic deletion models, we found that IL-13 signaling specifically to macrophages mediated cardiac functional recovery after MI in adult mice. Single transcriptomics revealed a subpopulation of cardiac macrophages in response to IL-13 administration. These IL-13–induced macrophages were highly efferocytotic and were identified by high IL-1R2 expression. Collectively, we elucidated a strongly proreparative role for IL-13 signaling directly to macrophages following cardiac injury. While this pathway is active in proregenerative neonatal stages, reactivation of macrophage IL-13 signaling is required to promote cardiac functional recovery in adults.

Authors

Santiago Alvarez-Argote, Samantha J. Paddock, Michael A. Flinn, Caelan W. Moreno, Makenna C. Knas, Victor A. Almeida, Sydney L. Buday, Amirala Bakhshian Nik, Michaela Patterson, Yi-Guang Chen, Chien-Wei Lin, Caitlin C. O’Meara

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Figure 7

IL-13/IL-4Rα reactivation in macrophages induces IL-1R2 expression in vivo.

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IL-13/IL-4Rα reactivation in macrophages induces IL-1R2 expression in vi...
(A and B) Feature plot of IL-1r2 expression in macrophages and violin plots of IL-1r2 expression in Mac0, Mac1, and Mac3 clusters. (C) Representative contour plots showing IL-1r2 expression in infiltrating cardiac macrophages at 4 dpi after MI. (D) Quantification of IL-1r2+ cardiac macrophage frequency at 4 dpi after MI. (E) Representative histograms showing tdTomato signal in cardiac resident macrophages from Myh6tdTomato mice treated with PBS versus rIL-13 after MI. (F) Quantification of tdTomato mean fluorescence intensity (MFI) in cardiac macrophages from Myh6tdTomato mice treated with PBS versus rIL-13 after MI. (G and H) Representative contour plots and quantification of tdTomato+ cardiac resident macrophages in Myh6tdTomato mice treated with PBS versus rIL-13 after MI. (I) Representative contour plots showing cardiac CD4 T cell populations in WT mice treated with PBS versus rIL-13 and control and IL-4RαMacKO mice treated with rIL-13 after MI. (J and K) Quantification of cardiac CD4 T cells frequencies after MI in WT mice, and control and IL-4RαMacKO mice treated with rIL-13 after MI. (L) Representative contour plots showing cardiac CD8 T cell populations in WT mice treated with PBS versus rIL-13 and control and IL-4RαMacKO mice treated with rIL-13 after MI. (M and N) Quantification of cardiac CD8 T cell frequencies in WT mice, and control and IL-4RαMacKO mice treated with rIL-13 after MI. Data are shown as mean ± SD. Each data point represents 1 mouse. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Comparison by 1-way ANOVA and Tukey’s post hoc test in D. Treatment effect by 2-way repeated-measures ANOVA and Sidak’s post hoc comparison in F and H. Time effect by 2-way ANOVA and Sidak’s post hoc comparison in J and M. Interaction effect of time and genotype by 2-way ANOVA and Sidak’s post hoc comparison in K and N.