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

Abstract

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.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.

Delayed persistence of elevated monocytic MDSC associates with deleterious outcomes in septic shock: a retrospective cohort study

“…Overall, the present results provide robust complementary information to that recently published by Hollen and colleagues [3]. Indeed, we observed that the persistence of increased M-MDSC after 1 week was significantly associated with worsening.…”

“…To the editor, Recent observations indicate that some septic patients, after inaugural inflammation, enter a stage of protracted immunosuppression that may take weeks/months to vanish and associate with increased rate of secondary infections and mortality [1]. Delayed elevation of myeloidderived suppressor cells (MDSC) has recently been hypothesized as a key mechanism sustaining sepsisinduced immunosuppression [2,3]. These cells constitute a heterogeneous population of immature myeloid cells characterized by their capacity to suppress T cell response [4].…”

Early Activation of Myeloid-Derived Suppressor Cells Participate in Sepsis-Induced Immune Suppression via PD-L1/PD-1 Axis

“…MDSCs will be recruited into inflamed tissues where they suppress acute inflammatory responses; however, long-term presence of MDSCs suppresses the host's immune system, and increases susceptibility to infection ( 43 ). Hollen observed that MDSCs kept elevating in sepsis survivors for at least 6 weeks after infection, but only MDSCs obtained 14 days and later post-sepsis had a significant suppressive function ( 44 ). In the current study, we counted the number of MDSCs in BM and spleen, and observed that the number of MDSCs from BM was small on day 1 post-CLP while increased significantly to a high level on day 3, which is considered entering the late stage of sepsis.…”

Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis

“…These specific genes are also important to the function of myeloid derived suppressor cells, which have been shown to be expanded and able to suppress T-cell function at Day 14 in septic patients. 35 Therefore, the gene signature seen in the both humans and mice at Day 14 appears to represent the continued expansion of immune cells secondary to a state of persistent low grade inflammation and immunosuppression after sepsis, especially in elderly patients whom are more likely to follow a clinical trajectory to CCI. 9,36 Interestingly, although this murine model of sepsis better recapitulates late human sepsis in mixed age cohorts, we found that the aged mice transcriptomic response to CLP + DCS still does not correlate better with the older adult human transcriptome after sepsis.…”