Myeloid-derived suppressor cell function and epigenetic expression evolves over time after surgical sepsis

Background Sepsis 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 b...

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Vydáno v:	Critical care (London, England) Ročník 23; číslo 1; s. 355 - 16
Hlavní autoři:	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.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 13.11.2019 BioMed Central Ltd BMC
Témata:	Aged Critical Care Medicine Emergency Medicine Epigenesis, Genetic - genetics Epigenesis, Genetic - physiology Epigenetic inheritance Epigenetics Female Health aspects Hospital patients Human Humans Immunotherapy Infection Intensive Intensive Care Units - organization & administration Intensive Care Units - statistics & numerical data Male Medicine Medicine & Public Health MicroRNA MicroRNAs - immunology MicroRNAs - metabolism Middle Aged miRNA Mortality Myeloid-derived suppressor cells Myeloid-Derived Suppressor Cells - immunology Myeloid-Derived Suppressor Cells - metabolism Sepsis Sepsis - complications Sepsis - physiopathology Surgery T cells Time Factors Human Immunosuppression Myeloid-derived suppressor cells Surgery Epigenetics Sepsis miRNA
ISSN:	1364-8535, 1466-609X, 1364-8535, 1466-609X
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Abstract	Background Sepsis 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. Methods Circulating 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. Results We 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. Conclusions We 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.
AbstractList	Abstract Background Sepsis 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. Methods Circulating 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. Results We 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. Conclusions We 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. Sepsis 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.BACKGROUNDSepsis 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.Circulating 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.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.We 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.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.We 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.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. Background Sepsis 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. Methods Circulating 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. Results We 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. Conclusions We 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. Sepsis 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. Circulating 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. We 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. We 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.
ArticleNumber	355
Audience	Academic
Author	Nacionales, Dina C. Leeuwenburgh, Christiaan Moldawer, Lyle L. Kladde, Michael Lopez, Maria-Cecilia Cox, Michael C. Mohr, Alicia M. Brakenridge, Scott Wu, Quran Gauthier, Marie-Pierre L. Brumback, Babette Darden, Dijoia Moore, Frederick A. Bihorac, Azra Efron, Philip A. Wang, Zhongkai Segal, Mark Ungaro, Ricardo Hollen, McKenzie K. Stortz, Julie A. Baker, Henry V. Hawkins, Russell B. Dirain, Marvin L. Rincon, Jaimar C.
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Snippet	Background Sepsis is an increasingly significant challenge throughout the world as one of the major causes of patient morbidity and mortality. Central to the... Sepsis is an increasingly significant challenge throughout the world as one of the major causes of patient morbidity and mortality. Central to the host... Abstract Background Sepsis is an increasingly significant challenge throughout the world as one of the major causes of patient morbidity and mortality. Central...
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SubjectTerms	Aged Critical Care Medicine Emergency Medicine Epigenesis, Genetic - genetics Epigenesis, Genetic - physiology Epigenetic inheritance Epigenetics Female Health aspects Hospital patients Human Humans Immunotherapy Infection Intensive Intensive Care Units - organization & administration Intensive Care Units - statistics & numerical data Male Medicine Medicine & Public Health MicroRNA MicroRNAs - immunology MicroRNAs - metabolism Middle Aged miRNA Mortality Myeloid-derived suppressor cells Myeloid-Derived Suppressor Cells - immunology Myeloid-Derived Suppressor Cells - metabolism Sepsis Sepsis - complications Sepsis - physiopathology Surgery T cells Time Factors
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Title	Myeloid-derived suppressor cell function and epigenetic expression evolves over time after surgical sepsis
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