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

Xianxiu Wan,Nisha Jain Garg,Imran Hussain Chowdhury,Zuliang Jie,Subhadip Choudhuri

doi:10.3390/cells9010080

Xianxiu Wan, Nisha Jain Garg + Show 3 more

Open Access

https://doi.org/10.3390/cells9010080

Copy DOI

Journal: Cells	Publication Date: Dec 28, 2019
Citations: 18	License type: CC BY 4.0

Affiliation: The University of Texas Medical Branch at Galveston

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.

Highlights

Trypanosoma cruzi (T. cruzi or Tc) is the etiological agent of Chagas disease (CD) that is the most frequent cause of heart failure and sudden death in Latin America [1]
These results suggested that a) embryonic cells are the major source of sinusoidal Mo/Mφ expansion during chronic T. cruzi infection, and b) Sirtuin 1 (SIRT1) agonist decreased the overall frequency of splenic F4/80+ Mφ in with SRT1720 had no significant effect on splenic cell total population in Chagas mice (Figure 2D); it resulted in 28% and 30% decline in the percentages of CD11b+ and CD11b+ F4/80+ Mo/Mφ, Cells 2020, 9, 80 respectively, in spleen of chronically infected mice
These results showed that splenic Mo/Mφ release of TNF-α, IL-6, and H2 O2 were increased by 151%, 124%, and 199%, respectively, in Chagas mice (Figure 4E–G, all, *** p < 0.001), and controlled by 53%, 42%, and 76%, respectively, when infected mice were treated with SRT1720 (Figure 4E–G, all, ˆp < 0.01)

Summary

Introduction

Trypanosoma cruzi (T. cruzi or Tc) is the etiological agent of Chagas disease (CD) that is the most frequent cause of heart failure and sudden death in Latin America [1]. The factors that drive progenitor cells to support Mφ response against acute T. cruzi infection and during chronic disease phase are not described. 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 detected in the myocardium of chronically infected mice. 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. SRT1720 reprogrammed the Tc-induced FAK-dependent transcription factors involved in Mφ proliferation and proinflammatory activation in Chagas disease

Objectives

Methods

Results

Discussion

Conclusion