{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T11:09:46Z","timestamp":1782472186280,"version":"3.54.5"},"reference-count":55,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,28]],"date-time":"2019-12-28T00:00:00Z","timestamp":1577491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI054578; R01AI136031"],"award-info":[{"award-number":["R01AI054578; R01AI136031"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Trypanosoma cruzi (Tc) causes Chagas disease (CD) that is the most frequent cause of heart failure in Latin America. TNF-\u03b1+ monocytes\/macrophages (Mo\/M\u03c6) are associated with inflammatory pathology in chronic CD. In this study, we determined the progenitor lineage of Mo\/M\u03c6 contributing to inflammation and examined the regulatory role of SIRT1 in modulating the Mo\/M\u03c6 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\/M\u03c6 were increased in sinusoidal compartment of Chagas mice. The splenic CD11b+ F4\/80+ Mo\/M\u03c6 of Chagas (vs. control) mice exhibited increased mRNA, protein, and surface expression of markers of proinflammatory phenotype (CD80+\/CD64+ &gt; CD200+\/CD206+) associated with proinflammatory cytokines response (IL-6+TNF-\u03b1 &gt;&gt; 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\/M\u03c6. SRT1720 did not alter the inherent capability of splenic Mo\/M\u03c6 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 M\u03c6 proliferation and migration and Notch1 involved in functional activation. Studies in cultured M\u03c6 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-\u03baB transcriptional activity and inflammatory cytokine gene expression in Tc-infected M\u03c6. Conclusions: The proinflammatory Mo\/M\u03c6 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 M\u03c6 proliferation and proinflammatory activation in Chagas disease.<\/jats:p>","DOI":"10.3390\/cells9010080","type":"journal-article","created":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T05:49:41Z","timestamp":1577684981000},"page":"80","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Origin of Monocytes\/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NF\u03baB-Dependent Proliferation and Proinflammatory Activation of Macrophages"],"prefix":"10.3390","volume":"9","author":[{"given":"Xianxiu","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imran Hussain","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuliang","family":"Jie","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhadip","family":"Choudhuri","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3453-2369","authenticated-orcid":false,"given":"Nisha Jain","family":"Garg","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX 77550, USA"},{"name":"Institute for Human Infections and Immunity, UTMB, Galveston, TX 77550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S1474-4422(10)70042-9","article-title":"Chagas disease and stroke","volume":"9","author":"Gascon","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101198","DOI":"10.1016\/j.redox.2019.101198","article-title":"Metabolic programming of macrophage functions and pathogens control","volume":"24","author":"Koo","year":"2019","journal-title":"Redox Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3389\/fimmu.2018.00202","article-title":"Pentose phosphate shunt modulates reactive oxygen species and nitric oxide production controlling Trypanosoma cruzi in macrophages","volume":"9","author":"Koo","year":"2018","journal-title":"Front. 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