Inhibition of Interleukin-21 prolongs the survival through the promotion of wound healing after myocardial infarction.

Ly6C macrophages promote scar formation and prevent early infarct expansion after myocardial infarction (MI). Although CD4 T cells influence the regulation of Ly6C macrophages after MI, the mechanism remains largely unknown. Based on the hypothesis that some molecule(s) secreted by CD4 T cells act on Ly6C macrophages, we searched for candidate molecules by focusing on cytokine receptors expressed on Ly6C macrophages. Comparing the transcriptome between Ly6C macrophages and Ly6C macrophages harvested from the infarcted heart, we found that Ly6C macrophages highly expressed the receptor for interleukin (IL)-21, a pleiotropic cytokine which is produced by several types of CD4 T cells, compared with Ly6C macrophages. Indeed, CD4 T cells harvested from the infarcted heart produce IL-21 upon stimulation. Importantly, the survival rate and cardiac function after MI were significantly improved in IL-21-deficient (il21) mice compared with those in wild-type (WT) mice. Transcriptome analysis of infarcted heart tissue from WT mice and il21 mice at 5 days after MI demonstrated that inflammation is persistent in WT mice compared with il21 mice. Consistent with the transcriptome analysis, the number of neutrophils and matrix metalloproteinase (MMP)-9 expression were significantly decreased, whereas the number of Ly6C macrophages and MMP-12 expression were significantly increased in il21 mice. In addition, collagen deposition and the number of myofibroblasts in the infarcted area were significantly increased in il21 mice. Consistently, IL-21 enhanced the apoptosis of Ly6C macrophages. Finally, administration of neutralizing IL-21 receptor Fc protein increased the number of Ly6C macrophages in the infarcted heart and improved the survival and cardiac function after MI. Thus, IL-21 decreases the survival after MI, possibly through the delay of wound healing by inducing the apoptosis of Ly6C macrophages.