Origin of Monocytes/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NFκB-Dependent Proliferation and Proinflammatory Activation of Macrophages
Background: <i>Trypanosoma cruzi (Tc)</i> causes Chagas disease (CD) that is the most frequent cause of heart failure in Latin America. TNF-α<sup>+</sup> monocytes/macrophages (Mo/Mφ) are associated with inflammatory pathology in chronic CD. In this study, w...
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MDPI AG
2019-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/1/80 |
| _version_ | 1797706245848694784 |
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| author | Xianxiu Wan Imran Hussain Chowdhury Zuliang Jie Subhadip Choudhuri Nisha Jain Garg |
| author_facet | Xianxiu Wan Imran Hussain Chowdhury Zuliang Jie Subhadip Choudhuri Nisha Jain Garg |
| author_sort | Xianxiu Wan |
| collection | DOAJ |
| description | Background: <i>Trypanosoma cruzi (Tc)</i> causes Chagas disease (CD) that is the most frequent cause of heart failure in Latin America. TNF-α<sup>+</sup> 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 <i>Tc</i>, 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<sup>+</sup> F4/80<sup>+</sup> Mo/Mφ were increased in sinusoidal compartment of Chagas mice. The splenic CD11b<sup>+</sup> F4/80<sup>+</sup> Mo/Mφ of Chagas (vs. control) mice exhibited increased mRNA, protein, and surface expression of markers of proinflammatory phenotype (CD80<sup>+</sup>/CD64<sup>+</sup> > CD200<sup>+</sup>/CD206<sup>+</sup>) 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 <i>Tc</i>-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 <i>Tc</i>-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 <i>Tc</i>-infected Mφ. Conclusions: The proinflammatory Mo/Mφ of yolk sac origin drive the splenic and tissue inflammatory response in chronic CD. SRT1720 reprogrammed the <i>Tc</i>-induced FAK-dependent transcription factors involved in Mφ proliferation and proinflammatory activation in Chagas disease. |
| first_indexed | 2024-03-12T05:49:24Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-12T05:49:24Z |
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| series | Cells |
| spelling | doaj.art-466324ba9b0d44d2af362a020c63fb722023-09-03T05:20:55ZengMDPI AGCells2073-44092019-12-01918010.3390/cells9010080cells9010080Origin of Monocytes/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NFκB-Dependent Proliferation and Proinflammatory Activation of MacrophagesXianxiu Wan0Imran Hussain Chowdhury1Zuliang Jie2Subhadip Choudhuri3Nisha Jain Garg4Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77550, USADepartment of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77550, USADepartment of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77550, USADepartment of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77550, USADepartment of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77550, USABackground: <i>Trypanosoma cruzi (Tc)</i> causes Chagas disease (CD) that is the most frequent cause of heart failure in Latin America. TNF-α<sup>+</sup> 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 <i>Tc</i>, 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<sup>+</sup> F4/80<sup>+</sup> Mo/Mφ were increased in sinusoidal compartment of Chagas mice. The splenic CD11b<sup>+</sup> F4/80<sup>+</sup> Mo/Mφ of Chagas (vs. control) mice exhibited increased mRNA, protein, and surface expression of markers of proinflammatory phenotype (CD80<sup>+</sup>/CD64<sup>+</sup> > CD200<sup>+</sup>/CD206<sup>+</sup>) 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 <i>Tc</i>-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 <i>Tc</i>-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 <i>Tc</i>-infected Mφ. Conclusions: The proinflammatory Mo/Mφ of yolk sac origin drive the splenic and tissue inflammatory response in chronic CD. SRT1720 reprogrammed the <i>Tc</i>-induced FAK-dependent transcription factors involved in Mφ proliferation and proinflammatory activation in Chagas disease.https://www.mdpi.com/2073-4409/9/1/80macrophage progenitorsros<i>trypanosoma cruzi</i>sirt1chagas diseasechronic inflammation |
| spellingShingle | Xianxiu Wan Imran Hussain Chowdhury Zuliang Jie Subhadip Choudhuri Nisha Jain Garg Origin of Monocytes/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NFκB-Dependent Proliferation and Proinflammatory Activation of Macrophages Cells macrophage progenitors ros <i>trypanosoma cruzi</i> sirt1 chagas disease chronic inflammation |
| title | Origin of Monocytes/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NFκB-Dependent Proliferation and Proinflammatory Activation of Macrophages |
| title_full | Origin of Monocytes/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NFκB-Dependent Proliferation and Proinflammatory Activation of Macrophages |
| title_fullStr | Origin of Monocytes/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NFκB-Dependent Proliferation and Proinflammatory Activation of Macrophages |
| title_full_unstemmed | Origin of Monocytes/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NFκB-Dependent Proliferation and Proinflammatory Activation of Macrophages |
| title_short | Origin of Monocytes/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NFκB-Dependent Proliferation and Proinflammatory Activation of Macrophages |
| title_sort | origin of monocytes macrophages contributing to chronic inflammation in chagas disease sirt1 inhibition of fak nfκb dependent proliferation and proinflammatory activation of macrophages |
| topic | macrophage progenitors ros <i>trypanosoma cruzi</i> sirt1 chagas disease chronic inflammation |
| url | https://www.mdpi.com/2073-4409/9/1/80 |
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