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.

Ly6C^低巨噬细胞促进瘢痕形成并防止心肌梗塞 (MI) 后早期梗塞扩大。尽管 CD4 ⁺ T 细胞影响 MI 后 Ly6C^低巨噬细胞的调节，但其机制仍然很大程度上未知。基于CD4 ⁺ T细胞分泌的一些分子作用于Ly6C^低巨噬细胞的假设，我们通过关注Ly6C^低巨噬细胞上表达的细胞因子受体来寻找候选分子。比较从梗塞心脏收获的 Ly6C^高巨噬细胞和 Ly6C^低巨噬细胞之间的转录组，我们发现 Ly6C^{低与 Ly6C高}巨噬细胞相比，巨噬细胞高度表达白细胞介素 (IL)-21 受体，白细胞介素 (IL)-21 是一种多效性细胞因子，由几种类型的 CD4 ⁺ T 细胞产生。事实上，从梗塞心脏收获的 CD4 ⁺ T 细胞在受到刺激时会产生 IL-21。重要的是，与野生型 (WT) 小鼠相比， IL-21 缺陷型 (il21 ^-/- ) 小鼠的心肌梗死后存活率和心脏功能显着改善。^{MI 后 5 天对 WT 小鼠和 il21 -/-}小鼠的梗塞心脏组织的转录组分析表明，与 il21 ^-/-相比，WT 小鼠的炎症持续存在老鼠。^{与转录组分析一致，在 il21 -/-}小鼠中，嗜中性粒细胞数量和基质金属蛋白酶 (MMP)-9 表达显着降低，而 Ly6C^低巨噬细胞数量和 MMP-12 表达显着增加。此外，在il21 ^-/-小鼠中，梗塞区域中的胶原沉积和肌成纤维细胞的数量显着增加。一致地，IL-21 增强了 Ly6C^低巨噬细胞的凋亡。最后，中和 IL-21 受体 Fc 蛋白的施用增加了 Ly6C^低的数量在梗死心脏中增加巨噬细胞，改善心肌梗死后的存活率和心功能。因此，IL-21 降低了 MI 后的存活率，可能是通过诱导 Ly6C^低巨噬细胞凋亡来延迟伤口愈合。