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

• DOI: 10.1172/jci.insight.172702
• Publication Date: 2023-12-05T17:00:40Z
• Authors: Santiago Alvarez-...; Samantha J. Paddock; Michael A. Flinn; Caelan W. Moreno; Makenna C. Knas; Victor A. Almeida; Sydney L. Buday; Amirala Bakhshian...; Michaela Patterson; Yi-Guang Chen; Chien-Wei Lin; Caitlin C. O’Meara
• Keywords: Mice; Interleukin-13; Macrophages; Receptors, Interleukin-13; Myocardial Infarction; Animals; Lymphocytes; Immunity, Innate; Research Article

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.