PMID- 36841467
OWN - NLM
STAT- MEDLINE
DCOM- 20230404
LR  - 20230404
IS  - 1090-2449 (Electronic)
IS  - 0014-4894 (Linking)
VI  - 248
DP  - 2023 May
TI  - Chronic Trypanosoma cruzi infection activates the TWEAK/Fn14 axis in cardiac 
      myocytes and fibroblasts driving structural and functional changes that affect 
      the heart.
PG  - 108491
LID - S0014-4894(23)00032-2 [pii]
LID - 10.1016/j.exppara.2023.108491 [doi]
AB  - 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 (NFkappaB) signaling. Ex vivo stimulation of both cell 
      types with recombinant TWEAK for 24 h boosted the NFkappaB-regulated production of 
      proinflammatory/profibrotic mediators (IL-1beta, IL-6, TNF-alpha, 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.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Santamaria, Miguel H
AU  - Santamaria MH
AD  - Laboratorio de Biologia Experimental, Centro de Estudios Metabolicos, Santander, 
      Cantabria, Spain.
FAU - Rios, Luisa Delgado
AU  - Rios LD
AD  - Laboratorio de Biologia Experimental, Centro de Estudios Metabolicos, Santander, 
      Cantabria, Spain.
FAU - Corral, Ricardo S
AU  - Corral RS
AD  - Instituto Multidisciplinario de Investigaciones en Patologias Pediatricas (IMIPP, 
      CONICET-GCBA), Servicio de Parasitologia-Chagas, Hospital de Ninos "Dr. Ricardo 
      Gutierrez", Buenos Aires, Argentina. Electronic address: 
      ricardocorral@conicet.gov.ar.
LA  - eng
PT  - Journal Article
DEP - 20230223
PL  - United States
TA  - Exp Parasitol
JT  - Experimental parasitology
JID - 0370713
RN  - 0 (TWEAK Receptor)
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Myocytes, Cardiac
MH  - TWEAK Receptor/metabolism
MH  - Mice, Inbred C57BL
MH  - NF-kappa B/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Inflammation
MH  - Fibroblasts
MH  - *Heart Diseases/metabolism
MH  - Hypertrophy/metabolism
MH  - *Chagas Disease
OTO - NOTNLM
OT  - Adverse remodeling
OT  - Chagas heart disease
OT  - Inflammation
OT  - TWEAK/Fn14 axis
OT  - Trypanosoma cruzi
COIS- Declarations of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/02/26 06:00
MHDA- 2023/04/04 06:42
CRDT- 2023/02/25 19:34
PHST- 2022/08/08 00:00 [received]
PHST- 2023/01/04 00:00 [revised]
PHST- 2023/02/18 00:00 [accepted]
PHST- 2023/04/04 06:42 [medline]
PHST- 2023/02/26 06:00 [pubmed]
PHST- 2023/02/25 19:34 [entrez]
AID - S0014-4894(23)00032-2 [pii]
AID - 10.1016/j.exppara.2023.108491 [doi]
PST - ppublish
SO  - Exp Parasitol. 2023 May;248:108491. doi: 10.1016/j.exppara.2023.108491. Epub 2023 
      Feb 23.