Origin of Monocytes/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NFκB-Dependent Proliferation and Proinflammatory Activation of Macrophages

摘要: Background: Trypanosoma cruzi (Tc) causes Chagas disease (CD) that is the most frequent cause of heart failure in Latin America. TNF-α+ monocytes/macrophages (Mo/Mφ) are associated with inflammatory pathology chronic CD. In this study, we determined progenitor lineage Mo/Mφ contributing to inflammation and examined regulatory role SIRT1 modulating response disease. Methods Results: C57BL/6 mice were infected Tc, treated agonist (SRT1720) after control acute parasitemia, monitored during phase (150 days post-infection). Flow cytometry studies showed an increase maturation bone marrow hematopoietic stem cell (HSC)-derived Mo proinflammatory anti-inflammatory phenotype acutely- chronically-infected mice; however, these cells not increased splenic compartment mice. Instead, yolk-sac-derived CD11b+ F4/80+ sinusoidal The (vs. control) exhibited mRNA, protein, surface expression markers (CD80+/CD64+ > CD200+/CD206+) cytokines (IL-6+TNF-α >> Arg-1+IL-10), also detected myocardium chronically Infected SRT1720 infected/untreated) decreased expansion myocardial infiltration Mo/Mφ. did alter inherent capability respond pathogen stimulus. dampened Tc-induced and/or phosphorylation focal adhesion kinase (FAK) downstream transcription factors (Pu.1, c-Myb, Runx1) involved Mφ proliferation migration Notch1 functional activation. Studies cultured confirmed agonistic effects controlling Tc-induced, FAK-dependent FAK inhibitor abrogated NF-κB transcriptional activity cytokine gene Tc-infected Mφ. Conclusions: yolk sac origin drive tissue reprogrammed activation