Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease

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Abstract

Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to study the role of endogenous OPN as a modulator of myocardial CCL5 chemokine and MMP-2 metalloproteinase, and its pathological impact in a murine model of Chagas heart disease. Wild-type (WT) and OPN-deficient (spp1 −/−) mice were parasite-infected (Brazil strain) for 100 days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 −/− infection showed lower heart-to-body ratio (P < 0.01) as well as reduced inflammatory pathology (P < 0.05), CCL5 expression (P < 0.05), myocyte size (P < 0.05) and fibrosis (P < 0.01) in cardiac tissues. Intense OPN labeling was observed in inflammatory cells recruited to infected heart (P < 0.05). Plasma concentration of MMP-2 was higher (P < 0.05) in infected WT than in spp1 −/− mice. Coincidently, specific immunostaining revealed increased gelatinase expression (P < 0.01) and activity (P < 0.05) in the inflamed hearts from T. cruzi WT mice, but not in their spp1 −/− littermates. CCL5 and MMP-2 induction occurred preferentially (P < 0.01) in WT heart-invading CD8+ T cells and was mediated via phospho-JNK MAPK signaling. Heart levels of OPN, CCL5 and MMP-2 correlated (P < 0.01) with collagen accumulation in the infected WT group only. Endogenous OPN emerges as a key player in the pathogenesis of chronic Chagas heart disease, through the upregulation of myocardial CCL5/MMP-2 expression and activities resulting in pro-inflammatory and pro-hypertrophic events, cardiac remodeling and interstitial fibrosis.

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Caballero, E. P., Santamaría, M. H., & Corral, R. S. (2018). Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1864(1), 11–23. https://doi.org/10.1016/j.bbadis.2017.10.006

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