Chronic Trypanosoma cruzi infection activates the TWEAK/Fn14 axis in cardiac myocytes and fibroblasts driving structural and functional changes that affect the heart

被引：1

作者：

Santamaria, Miguel H. ^{[1
]}

Rios, Luisa Delgado ^{[1
]}

Corral, Ricardo S. ^{[2
,3
]}

机构：

[1] Ctr Estudios Metab, Lab Biol Expt, Santander, Cantabria, Spain

[2] Consejo Nacl Invest Cient & Tecn, Hosp Ninos Dr Ricardo Gutierrez, Serv Parasitol Chagas, Inst Multidisciplinario Invest Patol Pediat IMIPP,, Buenos Aires, Argentina

[3] Hosp Ninos Dr Ricardo Gutierrez, Serv Parasitol Chagas, Ciudad Autonoma Buenos Aires, Inst Multidisciplinario Invest Patol Pediat IMIPP, 1330 Gallo, RA-1425 Buenos Aires, Argentina

来源：

EXPERIMENTAL PARASITOLOGY | 2023年 / 248卷

关键词：

Trypanosoma cruzi; Chagas heart disease; TWEAK; Fn14; axis; Inflammation; Adverse remodeling; CYTOKINE-RECEPTOR AXIS; NECROSIS-FACTOR-ALPHA; CHAGAS-DISEASE; WEAK INDUCER; EXPRESSION; FN14; APOPTOSIS; CARDIOMYOCYTES; INFLAMMATION; DYSFUNCTION;

D O I：

10.1016/j.exppara.2023.108491

中图分类号：

R38 [医学寄生虫学]; Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ; 100103 ;

摘要：

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 (NF kappa B) signaling. Ex vivo stimulation of both cell types with re-combinant TWEAK for 24 h boosted the NF kappa B-regulated production of proinflammatory/profibrotic mediators (IL-1 beta, IL-6, TNF-alpha, IL-8, CCL2, CCL5, MMP-2, MMP-9, ICAM-1, E-selectin) involved in chronic T. cruzi cardio-myopathy. 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.

引用

页数：10