Interleukin 4/13 signaling in cardiac regeneration and repair

Abstract

Interleukin 4 (IL4) and interleukin 13 (IL13) are closely related cytokines that have been classically attributed to type II immunity, namely, differentiation of T-helper 2 (T_H2) cells and alternative activation of macrophages. Although the role of IL4/13 has been well described in various contexts such as defense against helminth parasites, pathogenesis of allergic disease, and several models of wound healing, relatively little is known about the role of IL4/13 in the heart following injury. Emerging literature has identified various roles for IL4/13 in animal models of cardiac regeneration as well as in the adult mammalian heart following myocardial injury. Notably, although IL4 and IL13 signal to hematopoietic cell types following myocardial infarction (MI) to promote wound healing phenotypes, there is substantial evidence that these cytokines can signal directly to non-hematopoietic cell types in the heart during development, homeostasis, and following injury. Comprehensive understanding of the molecular and cellular actions of IL4/13 in the heart is still lacking, but overall evidence to date suggests that activation of these cytokines results in beneficial outcomes with respect to cardiac repair. Here, we aim to comprehensively review the role of IL4 and IL13 and their prospective mechanisms in cardiac regeneration and repair.

Keywords: interleukin; myocardial infarction; regeneration.

Figure 1.

Schematic representation of IL4 and IL13 receptors and associated downstream signaling pathways. Created with BioRender.com, and published with permission.

Figure 2.

Summary of reported genetic deletion models of IL14/13 cytokines and receptors in the mouse model and the phenotypic outcomes. IL13Rα1 global deletion (A), IL4/13 or IL13 global cytokine deletion (B), IL4Rα global deletion (C), and IL4Rα CM-specific (D) or IL4/13 or IL4Rα myeloid-specific (E) deletion. Created with BioRender.com, and published with permission.