{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:07:09Z","timestamp":1792789629667,"version":"4.5.0"},"reference-count":36,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:00:00Z","timestamp":1758672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CMIT"},{"name":"RICAI"},{"DOI":"10.13039\/501100001704","name":"ESCMID","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001704","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Community-acquired pneumonia (CAP) is a leading cause of death, with mortality linked to an unbalanced host response. Sirtuin (Sirt)1, a histone deacetylase, regulating metabolism and epigenetics, may be fundamental in activating the innate immune response. Sirt1 mRNA expression was significantly reduced in monocytes from CAP patients (n = 76) upon admission compared to healthy controls (n = 42), with levels returning to normal after 30 days. Pharmacological activation of Sirt1 with SRT1720 decreased LPS- and K. pneumoniae-induced IL-6 release in primary human monocytes and decreased NF-\u03baB activation in THP1 cells. In a mouse K. pneumoniae pneumosepsis model, SRT1720 strongly reduced neutrophil influx and degranulation markers in bronchoalveolar lavage fluid, lowered pulmonary concentrations of IL-6 and TNF-\u03b1, and reduced lung pathology scores. Simultaneously, it reduced neutrophil content in liver tissue and plasma transaminase levels, alongside a trend toward reduced liver necrosis. Plasma IL-6 and TNF-\u03b1 were significantly lower in SRT1720-treated mice at 42 h. Finally, while SRT1720 did not impact bacterial loads in the lungs, it reduced bacterial burden in blood, with a similar trend observed in liver homogenates. In conclusion, the Sirt1 activator SRT1720 exerts anti-inflammatory effects on human monocytes, reduces local and systemic inflammation and organ injury, and diminishes bacterial dissemination in murine pneumosepsis.<\/jats:p>","DOI":"10.3390\/ijms26199309","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T08:19:45Z","timestamp":1758701985000},"page":"9309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Sirt1 Activator SRT1720 Mitigates Human Monocyte Activation and Improves Outcome During Gram-Negative Pneumosepsis in Mice"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6541-2434","authenticated-orcid":false,"given":"Mathieu","family":"Blot","sequence":"first","affiliation":[{"name":"Center of Infection & Molecular Medicine, Amsterdam University Medical Center, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"D\u00e9partement de Maladies Infectieuse, H\u00f4pital Universitaire Dijon-Bourgogne, 21079 Dijon, France"},{"name":"Labex LipSTIC, LNC UMR1231, INSERM, Universit\u00e9 Bourgogne-Europe, 21078 Dijon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2131-5760","authenticated-orcid":false,"given":"Valentine","family":"L\u00e9opold","sequence":"additional","affiliation":[{"name":"Center of Infection & Molecular Medicine, Amsterdam University Medical Center, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"de Beer","sequence":"additional","affiliation":[{"name":"Center of Infection & Molecular Medicine, Amsterdam University Medical Center, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Florquin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe M.","family":"Butler","sequence":"additional","affiliation":[{"name":"Center of Infection & Molecular Medicine, Amsterdam University Medical Center, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelis","family":"van\u2019t Veer","sequence":"additional","affiliation":[{"name":"Center of Infection & Molecular Medicine, Amsterdam University Medical Center, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2472-3014","authenticated-orcid":false,"given":"Alex F.","family":"de Vos","sequence":"additional","affiliation":[{"name":"Center of Infection & Molecular Medicine, Amsterdam University Medical Center, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"van der Poll","sequence":"additional","affiliation":[{"name":"Center of Infection & Molecular Medicine, Amsterdam University Medical Center, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Division of Infectious Diseases, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41572-021-00259-0","article-title":"Pneumonia","volume":"7","author":"Torres","year":"2021","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.cmet.2017.06.001","article-title":"Specific and Complex Reprogramming of Cellular Metabolism in Myeloid Cells during Innate Immune Responses","volume":"26","author":"Stienstra","year":"2017","journal-title":"Cell Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nri.2016.136","article-title":"Disease tolerance and immunity in host protection against infection","volume":"17","author":"Soares","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1089\/sur.2015.262","article-title":"Biology and Metabolism of Sepsis: Innate Immunity, Bioenergetics, and Autophagy","volume":"17","author":"Lewis","year":"2016","journal-title":"Surg. Infect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.cbpa.2019.01.023","article-title":"Updates on the epigenetic roles of sirtuins","volume":"51","author":"Kosciuk","year":"2019","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ejmech.2018.10.028","article-title":"An overview of Sirtuins as potential therapeutic target: Structure, function and modulators","volume":"161","author":"Wang","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1080\/14728222.2020.1743268","article-title":"Sirtuins: Potential therapeutic targets for regulating acute inflammatory response?","volume":"24","author":"Vachharajani","year":"2020","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4712","DOI":"10.1128\/MCB.00657-10","article-title":"Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress","volume":"30","author":"Schug","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Yang, Y., Liu, Y., Wang, Y., Chao, Y., Zhang, J., Jia, Y., Tie, J., and Hu, D. (2022). Regulation of SIRT1 and Its Roles in Inflammation. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.831168"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.15252\/embj.201695737","article-title":"SIRT1 regulates macrophage self-renewal","volume":"36","author":"Imperatore","year":"2017","journal-title":"EMBO J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"110398","DOI":"10.1016\/j.cellsig.2022.110398","article-title":"SIRT1 ameliorated septic associated-lung injury and macrophages apoptosis via inhibiting endoplasmic reticulum stress","volume":"97","author":"Wang","year":"2022","journal-title":"Cell. Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41392-022-01232-3","article-title":"Metformin suppresses calcium oxalate crystal-induced kidney injury by promoting Sirt1 and M2 macrophage-mediated anti-inflammatory activation","volume":"8","author":"Liu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"You, J., Li, Y., and Chong, W. (2024). The role and therapeutic potential of SIRTs in sepsis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1394925"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.bbadis.2017.12.029","article-title":"SIRT1 regulates inflammation response of macrophages in sepsis mediated by long noncoding RNA","volume":"1864","author":"Jia","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1097\/SHK.0000000000000225","article-title":"Novel role of resveratrol: Suppression of high-mobility group protein box 1 nucleocytoplasmic translocation by the upregulation of sirtuin 1 in sepsis-induced liver injury","volume":"42","author":"Xu","year":"2014","journal-title":"Shock"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gao, R., Chen, J., Hu, Y., Li, Z., Wang, S., Shetty, S., and Fu, J. (2014). Sirt1 deletion leads to enhanced inflammation and aggravates endotoxin-induced acute kidney injury. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098909"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1097\/TA.0000000000003751","article-title":"Sirtuin 1 deletion increases inflammation and mortality in sepsis","volume":"93","author":"Labiner","year":"2022","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e199","DOI":"10.1097\/CCM.0000000000000949","article-title":"The Selective Sirtuin 1 Activator SRT2104 Reduces Endotoxin-Induced Cytokine Release and Coagulation Activation in Humans","volume":"43","author":"Scicluna","year":"2015","journal-title":"Crit. Care Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1097\/TA.0000000000004212","article-title":"SIRT1 downregulation in pneumonia is associated with an immature neutrophil response and increased disease severity","volume":"96","author":"Labiner","year":"2024","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/s13073-021-00948-1","article-title":"An epigenetic and transcriptomic signature of immune tolerance in human monocytes through multi-omics integration","volume":"13","author":"Brands","year":"2021","journal-title":"Genome Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/nature06261","article-title":"Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes","volume":"450","author":"Milne","year":"2007","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1111\/j.1365-2141.2011.08888.x","article-title":"Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells","volume":"155","author":"Chauhan","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1182\/blood-2017-06-788067","article-title":"Platelet glycoprotein VI aids in local immunity during pneumonia-derived sepsis caused by gram-negative bacteria","volume":"131","author":"Claushuis","year":"2018","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Achouiti, A., Vogl, T., Urban, C.F., R\u00f6hm, M., Hommes, T.J., van Zoelen, M.A.D., Florquin, S., Roth, J., van\u2019t Veer, C., and de Vos, A.F. (2012). Myeloid-related protein-14 contributes to protective immunity in gram-negative pneumonia derived sepsis. PLoS Pathog, 8.","DOI":"10.1371\/journal.ppat.1002987"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Qin, W., Liu, Z., van der Poll, T., and de Vos, A.F. (2022). Induction of Acute or Disseminating Bacterial Pneumonia in Mice and Sampling of Infected Organs for Studying the Host Response to Bacterial Pneumonia. Bio-Protocol, 12.","DOI":"10.21769\/BioProtoc.4287"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/path.5601","article-title":"Interleukin-33 improves local immunity during Gram-negative pneumonia by a combined effect on neutrophils and inflammatory monocytes","volume":"253","author":"Blok","year":"2021","journal-title":"J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"87","DOI":"10.14348\/molcells.2016.2318","article-title":"Sirt1 and the Mitochondria","volume":"39","author":"Tang","year":"2016","journal-title":"Mol. Cells"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Li, X., Li, Y., Hao, Q., Jin, J., and Wang, Y. (2024). Metabolic mechanisms orchestrated by Sirtuin family to modulate inflammatory responses. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1448535"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"S\u00f4nego, F., Castanheira, F.V.E.S., Ferreira, R.G., Kanashiro, A., Leite, C.A.V.G., Nascimento, D.C., Col\u00f3n, D.F., Borges, V.d.F., Alves-Filho, J.C., and Cunha, F.Q. (2016). Paradoxical Roles of the Neutrophil in Sepsis: Protective and Deleterious. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00155"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9723","DOI":"10.1080\/21655979.2021.1987132","article-title":"Overexpressing long non-coding RNA OIP5-AS1 ameliorates sepsis-induced lung injury in a rat model via regulating the miR-128-3p\/Sirtuin-1 pathway","volume":"12","author":"Xie","year":"2021","journal-title":"Bioengineered"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"444","DOI":"10.3109\/15412555.2014.974740","article-title":"Sirtuin 1 Activator SRT1720 Protects Against Lung Injury via Reduction of Type II Alveolar Epithelial Cells Apoptosis in Emphysema","volume":"12","author":"Gu","year":"2015","journal-title":"COPD"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4082102","DOI":"10.1155\/2017\/4082102","article-title":"Sirt1 Protects Endothelial Cells against LPS-Induced Barrier Dysfunction","volume":"2017","author":"Zhang","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/s41401-018-0045-3","article-title":"Activation of SIRT1 ameliorates LPS-induced lung injury in mice via decreasing endothelial tight junction permeability","volume":"40","author":"Fu","year":"2019","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1016\/j.immuni.2021.10.012","article-title":"The immunology of sepsis","volume":"54","author":"Wiersinga","year":"2021","journal-title":"Immunity"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8340","DOI":"10.1074\/jbc.M109.088682","article-title":"SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1","volume":"285","author":"Pacholec","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pradhan, K., Yi, Z., Geng, S., and Li, L. (2021). Development of Exhausted Memory Monocytes and Underlying Mechanisms. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.778830"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9309\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T04:12:15Z","timestamp":1758946335000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9309"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,24]]},"references-count":36,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26199309"],"URL":"https:\/\/doi.org\/10.3390\/ijms26199309","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,24]]}}}