The combined action of glycoinositolphospholipid from Trypanosoma cruzi and macrophage migration inhibitory factor increases proinflammatory mediator production by cardiomyocytes and vascular endothelial cells.

Autor: Rigazio CS; Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas (IMIPP, CONICET-GCBA), Servicio de Parasitología-Chagas, Hospital de Niños 'Dr. Ricardo Gutiérrez', Buenos Aires, Argentina., Mariz-Ponte N; Instituto de Investigação Biomédica, Universidade de Coimbra, Coimbra, Portugal., Pérez Caballero E; Laboratorio de Biología Experimental, Centro de Estudios Metabólicos, Santander, Spain., Penas FN; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina., Goren NB; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina., Santamaría MH; Laboratorio de Biología Experimental, Centro de Estudios Metabólicos, Santander, Spain., Corral RS; Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas (IMIPP, CONICET-GCBA), Servicio de Parasitología-Chagas, Hospital de Niños 'Dr. Ricardo Gutiérrez', Buenos Aires, Argentina. Electronic address: ricardocorral@conicet.gov.ar.
Jazyk: angličtina
Zdroj: Microbial pathogenesis [Microb Pathog] 2022 Dec; Vol. 173 (Pt A), pp. 105881. Date of Electronic Publication: 2022 Nov 12.
DOI: 10.1016/j.micpath.2022.105881
Abstrakt: Cardiomyopathy is the most serious complication of chronic Chagas disease, caused by infection with the protozoan Trypanosoma cruzi. Exacerbated inflammation of the myocardium constitutes a major pathologic component of the disease. In the myocardial microenvironment, parasite antigens and host inflammatory mediators may aggravate tissue damage. The glycoinositolphospholipid (GIPL) from T. cruzi is an inflammation-eliciting antigen recognized by Toll-like receptor 4 (TLR4), whereas the proinflammatory cytokine macrophage migration inhibitory factor (MIF) promotes progression of chronic Chagas cardiomyopathy. We herein aimed to examine the involvement of GIPL and MIF in molecular mechanisms leading to a pathogenic inflammatory response in HL-1 cardiomyocytes and HMEC microvascular endothelial cells. Immunofluorescence analysis revealed that GIPL enhanced TLR4 expression in both cell types. We found that TLR4/GIPL interaction and MIF activity modulated the arachidonic acid pathway implicated in persistent inflammation. The combination of GIPL at 50 μg/ml and MIF at 50 ng/ml upregulated type 2 cyclooxygenase (COX-2) levels in HL-1 and HMEC cells, in a stronger way than each molecule acting independently. Moreover, increased expression of prostanoid synthases and release of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) were detected in stimulated cells. Transfection experiments in HL-1 and HMEC cells showed that COX-2 induction was transcriptionally regulated through GIPL-TLR4 engagement and NFκB signaling cascade. (GIPL + MIF)-triggered NFκB activation was markedly attenuated by treatment with 100 μM Fenofibrate, a PPAR-α ligand. Fenofibrate reduced COX-2-dependent generation of bioactive lipids in HL-1 and HMEC cells. In addition, Fenofibrate abolished (GIPL + MIF)-fostered release of NO, IL-1β, IL-6, TNF-α, and CCL2. The combined actions of GIPL and MIF display potential for amplifying the inflammatory response in myocardium of parasite-infected hosts. Our current findings might help develop more effective measures to ameliorate cardiovascular abnormalities associated with Chagas heart disease.
Competing Interests: Declaration 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.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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