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dc.contributor.author
Santamaría, Miguel H.
dc.contributor.author
Corral, Ricardo Santiago
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dc.date.available
2024-02-20T15:00:03Z
dc.date.issued
2023-03
dc.identifier.citation
Santamaría, Miguel H.; Corral, Ricardo Santiago; Chronic Trypanosoma cruzi infection activates the TWEAK/Fn14 axis in cardiac myocytes and fibroblasts driving structural and functional changes that affect the heart; Academic Press Inc Elsevier Science; Experimental Parasitology; 248; 108491; 3-2023; 1-10
dc.identifier.issn
0014-4894
dc.identifier.uri
http://hdl.handle.net/11336/227651
dc.description.abstract
Sustained interaction between the cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its functional receptor, fibroblast growth factor-inducible 14 (Fn14), has been linked to cardiovascular disorders. Chagas cardiomyopathy, elicited by Trypanosoma cruzi infection, is associated with chronic inflammation, fibrosis and hypertrophy. This study aimed to explore the involvement of the TWEAK/Fn 14 axis in development of Chagas heart disease. Parasite infection in vitro triggered Fn14 overexpression in atrial HL-1 myocytes and cardiac MCF fibroblasts. Fn14 levels were also increased in heart tissue from C57BL/6 mice at 130 days post-infection, particularly in myocytes and fibroblasts. Concurrently, TWEAK expression in circulating monocytes from this group was higher than that determined in uninfected controls. TWEAK/Fn14 interaction was functional in myocytes and fibroblasts isolated from infected hearts, leading to TNF receptor-associated factor 2 (TRAF2)-mediated activation of nuclear factor kappa B (NFκB) signaling. Ex vivo stimulation of both cell types with recombinant TWEAK for 24 h boosted the NFκB-regulated production of proinflammatory/profibrotic mediators (IL-1β, IL-6, TNF-α, IL-8, CCL2, CCL5, MMP-2, MMP-9, ICAM-1, E-selectin) involved in chronic T. cruzi cardiomyopathy. We further evaluated the therapeutic potential of the soluble decoy receptor Fn14-Fc to interfere with TWEAK/Fn14-dependent pathogenic activity. Fn14-Fc treatment of chronically infected mice was effective in neutralizing the ligand and reverting electrocardiographic abnormalities, maladaptive inflammation, adverse remodeling and hypertrophy in myocardium. Altogether, these findings suggest that sustained TWEAK/Fn14 induction by persistent T. cruzi infection is implicated in cardiopathogenesis and make TWEAK/Fn14 axis a promising target for the treatment of chronic Chagas heart disease.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Academic Press Inc Elsevier Science
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dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
ADVERSE REMODELING
dc.subject
CHAGAS HEART DISEASE
dc.subject
INFLAMMATION
dc.subject
TRYPANOSOMA CRUZI
dc.subject
TWEAK/FN14 AXIS
dc.subject.classification
Inmunología
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dc.subject.classification
Medicina Básica
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dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
Chronic Trypanosoma cruzi infection activates the TWEAK/Fn14 axis in cardiac myocytes and fibroblasts driving structural and functional changes that affect the heart
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2024-02-20T13:23:22Z
dc.journal.volume
248
dc.journal.number
108491
dc.journal.pagination
1-10
dc.journal.pais
Estados Unidos
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dc.description.fil
Fil: Santamaría, Miguel H.. Centro de Estudios Metabólicos; España
dc.description.fil
Fil: Corral, Ricardo Santiago. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina
dc.journal.title
Experimental Parasitology
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0014489423000322
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1016/j.exppara.2023.108491
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