Signaling of IL13 through IL4Ra Promotes Cardiac Regeneration

Abstract

IntroductionDuring the first week of life, neonatal mice are able to regenerate their hearts after injury with minimal scarring. Our lab has previously published that the global knockout of anti‐inflammatory cytokine Interleukin 13 (IL13) inhibits neonatal cardiac regeneration in mice. IL13 primarily acts through the IL4Ra/IL13Ra1 heterodimer receptor to promote cell cycle activity. However, how IL13 specifically signals in the heart to promote this phenotype remains unexplored. We hypothesize that the deletion of the IL4Ra component of IL13's receptor complex will lead to a similar lack of regeneration in the mouse heart.MethodsTo delineate IL13 signaling mechanisms in the mouse, we utilized various knockouts of IL13 signaling—IL13 global knockout mice, IL4Ra global knockout mice, and C57/BL6 wildtype mice. With cardiomyocytes (CMs) isolated from these models, we analyzed the dynamics of downstream factors of recombinant IL13 (rIL13) in vitro. Additionally, at postnatal day 1 (P1), our mouse models were given apical resections to remove up to 10% of the apex of the heart. After resection, we investigated mRNA and protein expression of downstream markers, as well as CM proliferation at different time points. We also analyzed overall regenerative potential through echocardiography and Gömöri trichrome staining.ResultsIn vitro administration of rIL13 to wildtype neonatal mouse CMs resulted in strong, but transient activation of AKT and ERK1/2, which have been shown to be pro‐survival and pro‐proliferative respectively. In our IL4Ra KO mice, we see an attenuation of this signaling. At 7 days post resection (dpr), we see a significant decrease in proliferating CMs from IL13 KO mice when compared to wildtype. Additionally, at 21dpr in vivo, we observe significant fibrotic apical scars in IL13 KO mice, indicating lack of cardiac regeneration.ConclusionFrom these results, our data suggests that depletion of IL13 and its receptor, IL4Ra, inhibits regenerative pathways in the heart.Support or Funding InformationAmerican Heart AssociationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.