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

Ly6C^low macrophages promote scar formation and prevent early infarct expansion after myocardial infarction (MI). Although CD4⁺ T cells influence the regulation of Ly6C^low macrophages after MI, the mechanism remains largely unknown. Based on the hypothesis that some molecule(s) secreted by CD4⁺ T cells act on Ly6C^low macrophages, we searched for candidate molecules by focusing on cytokine receptors expressed on Ly6C^low macrophages. Comparing the transcriptome between Ly6C^high macrophages and Ly6C^low macrophages harvested from the infarcted heart, we found that Ly6C^low 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^high 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^low 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^low macrophages. Finally, administration of neutralizing IL-21 receptor Fc protein increased the number of Ly6C^low 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^low macrophages.