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

摘要

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 (sppl -/-) mice were parasite-infected (Brazil strain) for 100 days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, sppl -/- 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 sppl -/- 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 sppl -/- littermates. CCL5 and MMP-2 induction occurred preferentially (P 0.01) in WT heart-invading CDS+ 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.