CD8+ T-cells negatively regulate inflammation post-myocardial infarction
CD8+ T-cells negatively regulate inflammation post-myocardial infarction
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DOI：
10.1152/ajpheart.00112.2019
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发表时间：
2019-09-01
影响因子：
4.8
通讯作者：
DeLeon-Pennell, Kristine Y.
中科院分区：
文献类型：
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作者：
Ilatovskaya, Daria, V;Pitts, Cooper;DeLeon-Pennell, Kristine Y.
尽管T细胞数量较低，但适应性免疫应答是心肌梗死（MI）后心脏伤口愈合的关键。我们假设CD 8（+）T细胞调节炎症反应，导致MI后存活率和心功能下降。我们对C57 BL/6 J和CD 8a（tm 1 mak）小鼠（功能性CD 8（+）T细胞缺乏）进行了冠状动脉左前降支永久性闭塞。与野生型（WT）相比，CD 8a（tm 1 mak）小鼠在MI后7天的存活率增加，并且在MI后7天的心脏生理学改善。尽管死亡率较低，但100%的CD 8a（tm 1 mak）组死于心脏破裂，而WT组仅为33%。苦天狼星红染色和胶原免疫印迹表明，在CD 8a（tm 1 mak）小鼠中，梗死区域以及远端区域的纤维化加速;然而，这种增加是由于可溶性胶原升高，涉及瘢痕形成不良。血浆和组织炎症加剧，如Cxcl 1、Ccl 11、基质金属蛋白酶（MMP）-2和MMP-9水平升高所示。免疫组织化学和流式细胞术表明，CD 8a（tm 1 mak）组在MI后第3天增加了中性粒细胞和巨噬细胞的数量，并在MI后第7天增加了肥大细胞标志物。在CD 8a（tm 1 mak）小鼠中，酪氨酸蛋白激酶MER的裂解增加，导致坏死组织的清除延迟。总之，尽管CD 8a（tm 1 mak）小鼠的心脏生理学和总体生存率有所改善，但先天性炎症增加，瘢痕形成不良，导致心脏破裂的发生率较高。我们的数据表明，CD 8（+）T细胞在心肌梗死后恢复中的作用可能对心脏重塑既有利又有害，并且是通过细胞特异性机制介导的。新&值得注意的是，我们确定了涉及CD 8（+）T细胞作为心肌梗死后（MI）伤口愈合过程调节剂的新机制。与野生型动物相比，没有功能性CD 8（+）T细胞的小鼠在MI后7天的心脏生理学和死亡率有所改善。尽管有更好的总体存活率，但缺乏功能性CD 8（+）T细胞的动物延迟了坏死组织的清除，导致瘢痕形成不良和心脏破裂增加，这表明CD 8（+）T细胞在心脏重塑过程中发挥双重作用。
The adaptive immune response is key for cardiac wound healing post-myocardial infarction (MI) despite low T-cell numbers. We hypothesized that CD8(+) T-cells regulate the inflammatory response, leading to decreased survival and cardiac function post-MI. We performed permanent occlusion of the left anterior descending coronary artery on C57BL/6J and CD8a(tm1mak) mice (deficient in functional CD8(+) T-cells). CD8a(tm1mak) mice had increased survival at 7 days post-MI compared with that of the wild-type (WT) and improved cardiac physiology at day 7 post-MI. Despite having less mortality, 100% of the CD8a(tm1mak) group died because of cardiac rupture compared with only 33% of the WT. Picrosirius red staining and collagen immunoblotting indicated an acceleration of fibrosis in the infarct area as well as remote area in the CD8a(tm1mak) mice; however, this increase was due to elevated soluble collagen implicating poor scar formation. Plasma and tissue inflammation were exacerbated as indicated by higher levels of Cxcl1, Ccl11, matrix metalloproteinase (MMP)-2, and MMP-9. Immunohistochemistry and flow cytometry indicated that the CD8a(tm1mak) group had augmented numbers of neutrophils and macrophages at post-MI day 3 and increased mast cell markers at post-MI day 7. Cleavage of tyrosine-protein kinase MER was increased in the CD8a(tm1mak) mice, resulting in delayed removal of necrotic tissue. In conclusion, despite having improved cardiac physiology and overall survival, CD8a(tm1mak) mice had increased innate inflammation and poor scar formation, leading to higher incidence of cardiac rupture. Our data suggest that the role of CD8(+) T-cells in post-MI recovery may be both beneficial and detrimental to cardiac remodeling and is mediated via a cell-specific mechanism.NEW & NOTEWORTHY We identified new mechanisms implicating CD8(+) T-cells as regulators of the post-myocardial infarction (MI) wound healing process. Mice without functional CD8(+) T-cells had improved cardiac physiology and less mortality 7 days post MI compared with wild-type animals. Despite having better overall survival, animals lacking functional CD8(+) T-cells had delayed removal of necrotic tissue, leading to poor scar formation and increased cardiac rupture, suggesting that CD8(+) T-cells play a dual role in the cardiac remodeling process.