Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, Florida, United States.
Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida, United States.
Am J Physiol Heart Circ Physiol. 2024 Aug 1;327(2):H533-H544. doi: 10.1152/ajpheart.00195.2024. Epub 2024 Jul 12.
The thymus, where T lymphocytes develop and mature, is sensitive to insults such as tissue ischemia or injury. The insults can cause thymic atrophy and compromise T-cell development, potentially impairing adaptive immunity. The objective of this study was to investigate whether myocardial infarction (MI) induces thymic injury to impair T lymphopoiesis and to uncover the underlying mechanisms. When compared with sham controls, MI mice at post-MI exhibited smaller thymus, lower cellularity, as well as less thymocytes at different developmental stages, indicative of T-lymphopoiesis impairment following MI. Accordingly, the spleen of MI mice has less T cells and recent thymic emigrants (RTEs), implying that the thymus of MI mice releases fewer mature thymocytes than sham controls. Interestingly, the secretory function of splenic T cells was not affected by MI. Further experiments showed that the reduction of thymocytes in MI mice was due to increased thymocyte apoptosis. Removal of adrenal glands by adrenalectomy (ADX) prevented MI-induced thymic injury and dysfunction, whereas corticosterone supplementation in ADX + MI mice reinduced thymic injury and dysfunction, indicating that glucocorticoids mediate thymic damage triggered by MI. Eosinophils play essential roles in thymic regeneration postirradiation, and eosinophil-deficient mice exhibit impaired thymic recovery after sublethal irradiation. Interestingly, the thymus was fully regenerated in both wild-type and eosinophil-deficient mice at post-MI, suggesting that eosinophils are not critical for thymus regeneration post-MI. In conclusion, our study demonstrates that MI-induced glucocorticoids trigger thymocyte apoptosis and impair T lymphopoiesis, resulting in less mature thymocyte release to the spleen. The thymus is essential for maintaining whole body T-cell output. Thymic injury can adversely affect T lymphopoiesis and T-cell immune response. This study demonstrates that MI induces thymocyte apoptosis and compromises T lymphopoiesis, resulting in fewer releases of mature thymocytes to the spleen. This process is mediated by glucocorticoids secreted by adrenal glands. Therefore, targeting glucocorticoids represents a novel approach to attenuate post-MI thymic injury.
胸腺是 T 淋巴细胞发育和成熟的场所，对组织缺血或损伤等损伤敏感。这些损伤可导致胸腺萎缩，损害 T 细胞发育，可能损害适应性免疫。本研究的目的是探讨心肌梗死 (MI) 是否会引起胸腺损伤，从而损害 T 细胞生成，并揭示潜在的机制。与假手术对照相比，MI 后小鼠的胸腺较小，细胞数量较少，不同发育阶段的胸腺细胞也较少，表明 MI 后 T 细胞生成受损。相应地，MI 小鼠的脾脏中 T 细胞和近期胸腺迁出细胞 (RTE) 较少，意味着 MI 小鼠的胸腺释放的成熟胸腺细胞比假手术对照少。有趣的是，MI 并未影响脾脏 T 细胞的分泌功能。进一步的实验表明，MI 小鼠胸腺细胞减少是由于胸腺细胞凋亡增加所致。通过肾上腺切除术 (ADX) 去除肾上腺可防止 MI 引起的胸腺损伤和功能障碍，而在 ADX+MI 小鼠中补充皮质酮可重新引起胸腺损伤和功能障碍，表明糖皮质激素介导 MI 引起的胸腺损伤。嗜酸性粒细胞在辐射后胸腺再生中起重要作用，而亚致死辐射后嗜酸性粒细胞缺乏小鼠的胸腺恢复受损。有趣的是，在 MI 后，野生型和嗜酸性粒细胞缺乏型小鼠的胸腺均完全再生，表明嗜酸性粒细胞对 MI 后胸腺再生并非至关重要。总之，本研究表明，MI 诱导的糖皮质激素触发胸腺细胞凋亡并损害 T 细胞生成，导致成熟的胸腺细胞向脾脏的释放减少。胸腺对于维持全身 T 细胞输出至关重要。胸腺损伤可对 T 细胞生成和 T 细胞免疫反应产生不利影响。本研究表明，MI 诱导胸腺细胞凋亡并损害 T 细胞生成，导致成熟的胸腺细胞向脾脏的释放减少。这一过程是由肾上腺分泌的糖皮质激素介导的。因此，靶向糖皮质激素可能是减轻 MI 后胸腺损伤的一种新方法。
