Chagas disease, caused by Trypanosoma cruzi, stands as the primary cause of dilated cardiomyopathy in the Americas. Macrophages play a crucial role in the heart’s response to infection. Given their functional and phenotypic adaptability, manipulating specific macrophage subsets could be vital in aiding essential cardiovascular functions including tissue repair and defense against infection. PPARα are ligand-dependent transcription factors involved in lipid metabolism and inflammation regulation. However, the role of fenofibrate, a PPARα ligand, in the activation profile of cardiac macrophages as well as its effect on the early inflammatory and fibrotic response in the heart remains unexplored. The present study demonstrates that fenofibrate significantly reduces not only the serum activity of tissue damage biomarker enzymes (LDH and GOT) but also the circulating proportions of pro-inflammatory monocytes (CD11b⁺ LY6C^high). Furthermore, both CD11b⁺ Ly6C^low F4/80^high macrophages (MΦ) and recently differentiated CD11b⁺ Ly6C^high F4/80^high monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206^high) in the hearts of fenofibrate-treated mice. This shift correlates with a reduction in fibrosis, inflammation, and restoration of ventricular function in the early stages of Chagas disease. These findings encourage the repositioning of fenofibrate as a potential ancillary immunotherapy adjunct to antiparasitic drugs, addressing inflammation to mitigate Chagas disease symptoms.

中文翻译：

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非诺贝特诱导心脏巨噬细胞亚群的消退并减轻急性恰加斯心肌炎

由克氏锥虫引起的恰加斯病是美洲扩张型心肌病的主要原因。巨噬细胞在心脏对感染的反应中发挥着至关重要的作用。鉴于其功能和表型适应性，操纵特定的巨噬细胞亚群对于帮助基本的心血管功能（包括组织修复和防御感染）可能至关重要。 PPARα 是参与脂质代谢和炎症调节的配体依赖性转录因子。然而，非诺贝特（一种 PPARα 配体）在心脏巨噬细胞激活过程中的作用及其对心脏早期炎症和纤维化反应的影响仍有待探索。本研究表明，非诺贝特不仅显着降低组织损伤生物标志物酶（LDH 和 GOT）的血清活性，而且还显着降低促炎单核细胞（CD11b ⁺ LY6C^高）的循环比例。此外，在非诺贝特治疗的小鼠心脏中， CD11b ⁺ Ly6C^低F4/80^高巨噬细胞 (MΦ) 和最近分化的 CD11b ⁺ Ly6C^高F4/80^高单核细胞衍生巨噬细胞 (MdMΦ) 都转向解析表型 (CD206 ^high ) 。这种转变与恰加斯病早期阶段纤维化、炎症的减少和心室功能的恢复相关。这些发现鼓励将非诺贝特重新定位为抗寄生虫药物的潜在辅助免疫治疗辅助药物，解决炎症以减轻恰加斯病症状。