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CCL3/Macrophage Inflammatory Protein-1α Is Dually Involved in Parasite Persistence and Induction of a TNF- and IFNγ-Enriched Inflammatory Milieu in Trypanosoma cruzi -Induced Chronic Cardiomyopathy.
- Source :
-
Frontiers in immunology [Front Immunol] 2020 Mar 03; Vol. 11, pp. 306. Date of Electronic Publication: 2020 Mar 03 (Print Publication: 2020). - Publication Year :
- 2020
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Abstract
- CCL3, a member of the CC-chemokine family, has been associated with macrophage recruitment to heart tissue and parasite control in the acute infection of mouse with Trypanosoma cruzi , the causative agent of Chagas disease. Here, we approached the participation of CCL3 in chronic chagasic cardiomyopathy (CCC), the main clinical form of Chagas disease. We induced CCC in C57BL/6 ( ccl 3 <superscript>+/+</superscript> ) and CCL3-deficient ( ccl 3 <superscript>-/-</superscript> ) mice by infection with the Colombian Type I strain. In ccl 3 <superscript>+/+</superscript> mice, high levels of CCL3 mRNA and protein were detected in the heart tissue during the acute and chronic infection. Survival was not affected by CCL3 deficiency. In comparison with ccl 3 <superscript>+/+</superscript> , chronically infected ccl 3 <superscript>-/-</superscript> mice presented reduced cardiac parasitism and inflammation due to CD8 <superscript>+</superscript> cells and macrophages. Leukocytosis was decreased in infected ccl 3 <superscript>-/-</superscript> mice, paralleling the accumulation of CD8 <superscript>+</superscript> T cells devoid of activated CCR5 <superscript>+</superscript> LFA-1 <superscript>+</superscript> cells in the spleen. Further, T. cruzi -infected ccl 3 <superscript>-/-</superscript> mice presented reduced frequency of interferon-gamma (IFNγ) <superscript>+</superscript> cells and numbers of parasite-specific IFNγ-producing cells, while the T. cruzi antigen-specific cytotoxic activity was increased. Stimulation of CCL3-deficient macrophages with IFNγ improved parasite control, in a milieu with reduced nitric oxide (NO <subscript>x</subscript> ) and tumor necrosis factor (TNF), but similar interleukin-10 (IL-10), concentrations. In comparison with chronically T. cruzi -infected ccl 3 <superscript>+/+</superscript> counterparts, ccl 3 <superscript>-/-</superscript> mice did not show enlarged heart, loss of left ventricular ejection fraction, QTc prolongation and elevated CK-MB activity. Compared with ccl 3 <superscript>+/+</superscript> , infected ccl 3 <superscript>-/-</superscript> mice showed reduced concentrations of TNF, while IL-10 levels were not affected, in the heart milieu. In spleen of ccl 3 <superscript>+/+</superscript> NI controls, most of the CD8 <superscript>+</superscript> T-cells expressing the CCL3 receptors CCR1 or CCR5 were IL-10 <superscript>+</superscript> , while in infected mice these cells were mainly TNF <superscript>+</superscript> . Lastly, selective blockage of CCR1/CCR5 (Met-RANTES therapy) in chronically infected ccl 3 <superscript>+/+</superscript> mice reversed pivotal electrical abnormalities (bradycardia, prolonged PR, and QTc interval), in correlation with reduced TNF and, mainly, CCL3 levels in the heart tissue. Therefore, in the chronic T. cruzi infection CCL3 takes part in parasite persistence and contributes to form a CD8 <superscript>+</superscript> T-cell and macrophage-enriched cardiac inflammation. Further, increased levels of CCL3 create a scenario with abundant IFNγ and TNF, associated with cardiomyocyte injury, heart dysfunction and QTc prolongation, biomarkers of severity of Chagas' heart disease.<br /> (Copyright © 2020 Gibaldi, Vilar-Pereira, Pereira, Silva, Barrios, Ramos, Mata dos Santos, Gazzinelli and Lannes-Vieira.)
- Subjects :
- Animals
CD8-Positive T-Lymphocytes drug effects
CD8-Positive T-Lymphocytes immunology
Cells, Cultured
Chagas Cardiomyopathy parasitology
Chagas Cardiomyopathy pathology
Chemokine CCL3 deficiency
Chemokine CCL3 pharmacology
Chemokine CCL5 pharmacology
Chemokine CCL5 therapeutic use
Chemotaxis, Leukocyte drug effects
Cytokines biosynthesis
Cytokines genetics
Cytokines pharmacology
Electrocardiography drug effects
Female
Interferon-gamma pharmacology
Macrophages, Peritoneal immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocarditis etiology
Myocarditis pathology
Myocarditis physiopathology
RNA, Messenger biosynthesis
Receptors, Chemokine antagonists & inhibitors
Receptors, Chemokine biosynthesis
Receptors, Chemokine genetics
Specific Pathogen-Free Organisms
Spleen immunology
Spleen metabolism
Stroke Volume
Trypanosoma cruzi isolation & purification
Tumor Necrosis Factor-alpha analysis
Chagas Cardiomyopathy physiopathology
Chemokine CCL3 physiology
Interferon-gamma physiology
Macrophages, Peritoneal parasitology
Parasitemia physiopathology
Trypanosoma cruzi physiology
Tumor Necrosis Factor-alpha physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 11
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 32194558
- Full Text :
- https://doi.org/10.3389/fimmu.2020.00306