Author:
Hollen McKenzie K.,Stortz Julie A.,Darden Dijoia,Dirain Marvin L.,Nacionales Dina C.,Hawkins Russell B.,Cox Michael C.,Lopez Maria-Cecilia,Rincon Jaimar C.,Ungaro Ricardo,Wang Zhongkai,Wu Quran,Brumback Babette,Gauthier Marie-Pierre L.,Kladde Michael,Leeuwenburgh Christiaan,Segal Mark,Bihorac Azra,Brakenridge Scott,Moore Frederick A.,Baker Henry V.,Mohr Alicia M.,Moldawer Lyle L.,Efron Philip A.
Abstract
AbstractBackgroundSepsis is an increasingly significant challenge throughout the world as one of the major causes of patient morbidity and mortality. Central to the host immunologic response to sepsis is the increase in circulating myeloid-derived suppressor cells (MDSCs), which have been demonstrated to be present and independently associated with poor long-term clinical outcomes. MDSCs are plastic cells and potentially modifiable, particularly through epigenetic interventions. The objective of this study was to determine how the suppressive phenotype of MDSCs evolves after sepsis in surgical ICU patients, as well as to identify epigenetic differences in MDSCs that may explain these changes.MethodsCirculating MDSCs from 267 survivors of surgical sepsis were phenotyped at various intervals over 6 weeks, and highly enriched MDSCs from 23 of these samples were co-cultured with CD3/CD28-stimulated autologous T cells. microRNA expression from enriched MDSCs was also identified.ResultsWe observed that MDSC numbers remain significantly elevated in hospitalized sepsis survivors for at least 6 weeks after their infection. However, only MDSCs obtained at and beyond 14 days post-sepsis significantly suppressed T lymphocyte proliferation and IL-2 production. These same MDSCs displayed unique epigenetic (miRNA) expression patterns compared to earlier time points.ConclusionsWe conclude that in sepsis survivors, immature myeloid cell numbers are increased but the immune suppressive function specific to MDSCs develops over time, and this is associated with a specific epigenome. These findings may explain the chronic and persistent immune suppression seen in these subjects.
Funder
National Institute of General Medical Sciences
Publisher
Springer Science and Business Media LLC
Subject
Critical Care and Intensive Care Medicine
Reference68 articles.
1. Mares CA, Sharma J, Ojeda SS, Li Q, Campos JA, Morris EG, et al. Attenuated response of aged mice to respiratory Francisella novicida is characterized by reduced cell death and absence of subsequent hypercytokinemia. PLoS One. 2010;5(11):e14088.
2. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10.
3. Plevin R, Callcut R. Update in sepsis guidelines: what is really new? Trauma Surg Acute Care Open. 2017;2(1):e000088.
4. National Inpatient Hospital Costs. The most expensive conditions by payer, 2013: Agency for Healthcare Research and Quality; 2016. Available from: https://www.hcup-us.ahrq.gov/reports/statbriefs/sb204-Most-Expensive-Hospital-Conditions.jsp. Accessed May 2019.
5. Seventieth World Health Assembly update, 26 May 2017 [press release]. World Health Organization, May 26, 2017 2017.
Cited by
64 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献