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

Cells. 2019 Dec 28;9(1):80. doi: 10.3390/cells9010080.

Abstract

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 in chronic CD. In this study, we determined the progenitor lineage of Mo/Mφ contributing to inflammation and examined the regulatory role of SIRT1 in modulating the Mo/Mφ response in Chagas disease.

Methods and results: C57BL/6 mice were infected with Tc, treated with SIRT1 agonist (SRT1720) after control of acute parasitemia, and monitored during chronic phase (150 days post-infection). Flow cytometry studies showed an increase in maturation of bone marrow hematopoietic stem cell (HSC)-derived Mo of proinflammatory and anti-inflammatory phenotype in acutely- and chronically-infected mice; however, these cells were not increased in splenic compartment of infected mice. Instead, yolk-sac-derived CD11b+ F4/80+ Mo/Mφ were increased in sinusoidal compartment of Chagas mice. The splenic CD11b+ F4/80+ Mo/Mφ of Chagas (vs. control) mice exhibited increased mRNA, protein, and surface expression of markers of proinflammatory phenotype (CD80+/CD64+ > CD200+/CD206+) associated with proinflammatory cytokines response (IL-6+TNF-α >> Arg-1+IL-10), and these were also detected in the myocardium of chronically infected mice. Infected mice treated with SRT1720 (vs. infected/untreated) exhibited decreased splenic expansion and myocardial infiltration of proinflammatory Mo/Mφ. SRT1720 did not alter the inherent capability of splenic Mo/Mφ of Chagas mice to respond to pathogen stimulus. Instead, SRT1720 dampened the Tc-induced increase in the expression and/or phosphorylation of focal adhesion kinase (FAK) and downstream transcription factors (Pu.1, c-Myb, and Runx1) involved in Mφ proliferation and migration and Notch1 involved in functional activation. Studies in cultured Mφ confirmed the agonistic effects of SIRT1 in controlling the Tc-induced, FAK-dependent increase in the expression of transcription factors and showed that SIRT1 agonist and FAK inhibitor abrogated the NF-κB transcriptional activity and inflammatory cytokine gene expression in Tc-infected Mφ.

Conclusions: The proinflammatory Mo/Mφ of yolk sac origin drive the splenic and tissue inflammatory response in chronic CD. SRT1720 reprogrammed the Tc-induced FAK-dependent transcription factors involved in Mφ proliferation and proinflammatory activation in Chagas disease.

Keywords: Chagas disease; ROS; SIRT1; Trypanosoma cruzi; chronic inflammation; macrophage progenitors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers
  • Chagas Disease / complications*
  • Chagas Disease / metabolism*
  • Chagas Disease / mortality
  • Chagas Disease / parasitology
  • Chronic Disease
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Disease Susceptibility
  • Female
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Granulocyte-Macrophage Progenitor Cells / metabolism
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Immunophenotyping
  • Inflammation / complications*
  • Inflammation / metabolism*
  • Inflammation / parasitology
  • Inflammation Mediators / metabolism
  • Macrophage Activation / immunology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Monocytes / drug effects
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Monocytes / pathology
  • NF-kappaB-Inducing Kinase
  • Protein Serine-Threonine Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Sirtuin 1 / metabolism

Substances

  • Biomarkers
  • Cytokines
  • Heterocyclic Compounds, 4 or More Rings
  • Inflammation Mediators
  • Reactive Oxygen Species
  • SRT1720
  • Focal Adhesion Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Sirtuin 1