Full Length ArticleLeukocyte glucocorticoid receptor expression and related transcriptomic gene signatures during early sepsis
Introduction
Sepsis, defined as a life-threatening organ dysfunction resulting from infection, causes huge financial burdens and has a high mortality rate worldwide [[1], [2], [3]]. The effectiveness of corticosteroid as an adjunctive therapy has remained controversial. Lower-dose hydrocortisone (200 mg per day) showed an earlier reversal of shock in patients. However, various clinical trials have shown conflicting results regarding whether mortality is reduced among patients with septic shock [[4], [5], [6], [7]], and systematic reviews and meta-analyses have not reached a consensus on whether to administer hydrocortisone to these patients [[8], [9], [10]].
The discrepancies between clinical trials and evidence may be attributed to the heterogeneity within the septic population, as patients are manifested with different pathophysiology course and comorbidities. Thus, it is difficult to identify patients who are most likely to benefit from corticosteroid prescription [11]. Consequently, focusing on the cortisol pathway itself might help to interpret the mechanisms in corticosteroids response variability and help for patient selection.
Glucocorticoid receptor (GR) mediates most intracellular effects of glucocorticoids. Upon ligand binding, GR translocates from the cytoplasm to the nucleus and binds specific DNA sequences to modulate transcriptional activation or repression [12]. The splice variant GRα is the ligand-binding functional subtype, whereas GRβ is a non-ligand binding and a dominant negative inhibitor of GRα [13]. Many studies demonstrated that GRα downregulation is a primary cause of acquired glucocorticoid (GC) resistance [14].
Sepsis is a highly heterogeneous syndrome with various subtypes [15,16]. The underlying molecular mechanisms are complex and remain elusive. It was reported that differences in GR levels, various gene expression patterns, and subtypes in individuals may be related to the observed different reactions to corticosteroids [13,17,18]. Moreover, studies have demonstrated the involvement of non-coding RNAs, such as microRNAs, in regulating immune patterns during sepsis [19]. MicroRNAs have also been reported to be involved in the regulation of immune response and GR function in a variety of diseases [20]. Therefore, we hypothesize that GR expression and related microRNAs (miRNAs) might also be responsible for different GR function and GC response during early sepsis.
Few large-scale studies have focused on GR expression and its underlying molecular mechanisms in humans. In the present study, we observed the original state of plasma adrenocorticotropic hormone (ACTH), cortisol concentrations, GR expression in several leukocyte subsets, GR-related mRNAs, and regulatory miRNAs in patients without glucocorticoid interventions. The goal of this study was, try to explain the molecular basis of GC response by determining the differences in GR expression and the regulatory genetic molecules during early sepsis, and try to provide new foundation for cortisol therapy. The research thereby may help to improve the understanding of cortisol response variability and to screen patients more plausibly to benefit from corticosteroid therapy during sepsis.
Section snippets
Study participants
This was an observational single-center cohort study. The study was conducted in the Emergency Department (ED) of Beijing Chaoyang Hospital, a tertiary teaching hospital in China. Patients meeting the sepsis 3.0 criteria [3] admitted to the emergency intensive care unit between October 2018 and August 2019 were enrolled. The patients were grouped into sepsis or septic shock groups based on the severity of their condition. Patients were excluded from the study if they were less than 18 years
Baseline characteristics of study participants
Clinical files and baseline characteristics of the study participants at day 1 are listed according to disease severity in Table 1 and outcome in Additional File 4: Table 1. A total of 40 healthy controls and 198 patients with sepsis were included in the cohort. The patients were divided into 121 sepsis cases and 77 septic shock cases based on severity. In addition, there were 128 survivors and 70 non-survivors according to the 28-day outcomes. The baseline characteristics of the populations
Discussion
In this study, we observed the levels of plasma hormones, GR receptor expression, and GR related genes in patients with sepsis. We found that GC levels in the sepsis, septic shock, and non-survival groups were significantly higher than those in the control and survival groups, whereas GR expression in circulating leukocyte subtype B cells, NK cells, and Tregs in patients with sepsis and septic shock was significantly lower compared to that in controls. In addition, the transcriptomic signature
Conclusions
Plasma cortisol was overproduced and GR was downregulated on most leukocyte subtypes in proportion with disease severity during sepsis and may account for the compromised glucocorticoid response observed during sepsis. The low expression of GR may be due to the alterations of regulatory genes. GR and related gene determination may provide help for selecting of appropriate patient cohort to optimize glucocorticoid treatment.
Consent to publication
Not applicable.
Funding
Not applicable.
Ethics approval
All the operations were in compliance with the ethics standards of Beijing Chaoyang Hospital. Informed consents for participation was obtained from patients or their legally authorized representatives. Ethical approval was acquired from Beijing Chaoyang Hospital Medical Ethics Committee.
Data or code availability
Not applicable.
Authors' contributions
CL conceived the study and participated in revising the manuscript and providing research funding. JL, ZT, MX, CH, and YY were involved in sample collection and the experimental process. JL collected data, drafted the manuscript, performed statistical analysis, and critically revised the manuscript. All authors consented to the publication of the manuscript and agreed to be responsible for the manuscript.
Authors' information
CL is the professor and Chairman of the Expert Steering Committee the Emergency and Critical Care Center of Beijing Friendship Hospital. JL was enrolled as an undergraduate in the Beijing Chaoyang Hospital and was transferred to Beijing Friendship Hospital with Professor CL. The study was performed in the ED department of Beijing Chaoyang Hospital.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Acknowledgements
The authors would like to thank the staff at the ED of Beijing Chaoyang Hospital for their help and support with sample and clinical data collection.
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