Javier Ruiz Luque, Ágata Carolina Cevey, Azul Victoria Pieralisi, Carolina Poncini, Fernando Erra Díaz, Marcus Vinicius Azevedo Reis, Martin Donato, Gerardo Ariel Mirkin, Nora Beatriz Goren and Federico Nicolás Penas*,
{"title":"非诺贝特能诱导心脏巨噬细胞亚群的解旋特征并减轻急性南美锥虫病心肌炎的症状","authors":"Javier Ruiz Luque, Ágata Carolina Cevey, Azul Victoria Pieralisi, Carolina Poncini, Fernando Erra Díaz, Marcus Vinicius Azevedo Reis, Martin Donato, Gerardo Ariel Mirkin, Nora Beatriz Goren and Federico Nicolás Penas*, ","doi":"10.1021/acsinfecdis.4c00125","DOIUrl":null,"url":null,"abstract":"<p >Chagas disease, caused by <i>Trypanosoma cruzi</i>, 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<sup>+</sup> LY6C<sup>high</sup>). Furthermore, both CD11b<sup>+</sup> Ly6C<sup>low</sup> F4/80<sup>high</sup> macrophages (MΦ) and recently differentiated CD11b<sup>+</sup> Ly6C<sup>high</sup> F4/80<sup>high</sup> monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206<sup>high</sup>) 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.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Fenofibrate Induces a Resolving Profile in Heart Macrophage Subsets and Attenuates Acute Chagas Myocarditis\",\"authors\":\"Javier Ruiz Luque, Ágata Carolina Cevey, Azul Victoria Pieralisi, Carolina Poncini, Fernando Erra Díaz, Marcus Vinicius Azevedo Reis, Martin Donato, Gerardo Ariel Mirkin, Nora Beatriz Goren and Federico Nicolás Penas*, \",\"doi\":\"10.1021/acsinfecdis.4c00125\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Chagas disease, caused by <i>Trypanosoma cruzi</i>, 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<sup>+</sup> LY6C<sup>high</sup>). Furthermore, both CD11b<sup>+</sup> Ly6C<sup>low</sup> F4/80<sup>high</sup> macrophages (MΦ) and recently differentiated CD11b<sup>+</sup> Ly6C<sup>high</sup> F4/80<sup>high</sup> monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206<sup>high</sup>) 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.</p>\",\"PeriodicalId\":17,\"journal\":{\"name\":\"ACS Infectious Diseases\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-04-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Infectious Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acsinfecdis.4c00125\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsinfecdis.4c00125","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Fenofibrate Induces a Resolving Profile in Heart Macrophage Subsets and Attenuates Acute Chagas Myocarditis
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+ LY6Chigh). Furthermore, both CD11b+ Ly6Clow F4/80high macrophages (MΦ) and recently differentiated CD11b+ Ly6Chigh F4/80high monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206high) 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.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.