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Liu P, Xiao Z, Lu X, Zhang X, Huang J. Regulatory B cells attenuate sepsis-associated pancreatic injury by regulating T cell homeostasis. Sci Rep 2025; 15:14424. [PMID: 40281196 PMCID: PMC12032014 DOI: 10.1038/s41598-025-98884-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 04/15/2025] [Indexed: 04/29/2025] Open
Abstract
Sepsis is a common and life-threatening syndrome resulting from systemic and dysregulated immune response to severe infection, which contributes to morbidity and mortality in critically ill patients. This work aimed to evaluate the regulatory function of Breg cells in sepsis-associated pancreatic injury. We established mice model of sepsis-associated pancreatic injury by cecal ligation and puncture (CLP). Pancreatic injury was assessed by measuring the levels of amylase activity and histologic pancreatic injury scores. The proportions of Breg cells and T cell subsets were analyzed by flow cytometry, their secreted cytokines were detected by ELISA. The expressions of T-bet, RORγt and Foxp3 in spleen were determined by RT-PCR. The apoptosis of pancreatic cells was examined by LDH assay and Tunel, and the cell viability was detected by MTT assay. Compared to the sham group, a significantly lower percentage of Breg cells was observed in model mice. Anti-CD22 treatment exacerbated pancreatic injury, and significantly increased the percentages of Th1, Th17 cells along with the levels of IFN-γ, IL-17 in CLP-induced sepsis model, but did not affect the differentiation of Treg cells and expression of IL-10. Anti-CD22 administration promoted the expressions of T-bet and RORγt, but did not affect the Foxp3 expression. Adoptive transfer Breg cells remarkably alleviated pancreatic injury, and significantly decreased the percentages of Th1, Th17 cells along with the levels of IFN-γ, IL-17 and further promoted the percentage of Treg cells and expression of IL-10 in CLP-induced sepsis model. Moreover, adoptive transfer Breg cells inhibited the expressions of T-bet and RORγt, and promoted Foxp3 expression in model mice. Lipopolysaccharide (LPS) promoted the apoptosis in pancreatic acinar cells, which was inhibited after culturing with Breg cells in vitro. LPS remarkably upregulated the differentiation of Th1 and Th17 cells, and downregulated the differentiation of Treg cells, which could be significantly reversed by Breg cells in vitro. In conclusion, Breg cells may exhibit the protective effects by modulating T cell responses along with the cytokines in sepsis-associated pancreatic injury.
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Affiliation(s)
- Pingping Liu
- Department of Emergency & Key Laboratory of Pediatric Emergency Medicine of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, 410007, Hunan, People's Republic of China
| | - Zhenghui Xiao
- Department of Emergency & Key Laboratory of Pediatric Emergency Medicine of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, 410007, Hunan, People's Republic of China.
| | - Xiulan Lu
- Department of Emergency & Key Laboratory of Pediatric Emergency Medicine of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, 410007, Hunan, People's Republic of China
| | - Xinping Zhang
- Department of Emergency & Key Laboratory of Pediatric Emergency Medicine of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, 410007, Hunan, People's Republic of China
| | - Jiaotian Huang
- Department of Emergency & Key Laboratory of Pediatric Emergency Medicine of Hunan Province, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, 410007, Hunan, People's Republic of China
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Yang L, Xuan R, Xu D, Sang A, Zhang J, Zhang Y, Ye X, Li X. Comprehensive integration of diagnostic biomarker analysis and immune cell infiltration features in sepsis via machine learning and bioinformatics techniques. Front Immunol 2025; 16:1526174. [PMID: 40129981 PMCID: PMC11931141 DOI: 10.3389/fimmu.2025.1526174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 02/14/2025] [Indexed: 03/26/2025] Open
Abstract
Introduction Sepsis, a critical medical condition resulting from an irregular immune response to infection, leads to life-threatening organ dysfunction. Despite medical advancements, the critical need for research into dependable diagnostic markers and precise therapeutic targets. Methods We screened out five gene expression datasets (GSE69063, GSE236713, GSE28750, GSE65682 and GSE137340) from the Gene Expression Omnibus. First, we merged the first two datasets. We then identified differentially expressed genes (DEGs), which were subjected to KEGG and GO enrichment analyses. Following this, we integrated the DEGs with the genes from key modules as determined by Weighted Gene Co-expression Network Analysis (WGCNA), identifying 262 overlapping genes. 12 core genes were subsequently selected using three machine-learning algorithms: random forest (RF), Least Absolute Shrinkage and Selection Operator (LASSO), and Support Vector Machine-Recursive Feature Elimination (SVW-RFE). The utilization of the receiver operating characteristic curve in conjunction with the nomogram model served to authenticate the discriminatory strength and efficacy of the key genes. CIBERSORT was utilized to evaluate the inflammatory and immunological condition of sepsis. Astragalus, Salvia, and Safflower are the primary elements of Xuebijing, commonly used in the clinical treatment of sepsis. Using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), we identified the chemical constituents of these three herbs and their target genes. Results We found that CD40LG is not only one of the 12 core genes we identified, but also a common target of the active components quercetin, luteolin, and apigenin in these herbs. We extracted the common chemical structure of these active ingredients -flavonoids. Through docking analysis, we further validated the interaction between flavonoids and CD40LG. Lastly, blood samples were collected from healthy individuals and sepsis patients, with and without the administration of Xuebijing, for the extraction of peripheral blood mononuclear cells (PBMCs). By qPCR and WB analysis. We observed significant differences in the expression of CD40LG across the three groups. In this study, we pinpointed candidate hub genes for sepsis and constructed a nomogram for its diagnosis. Discussion This research not only provides potential diagnostic evidence for peripheral blood diagnosis of sepsis but also offers insights into the pathogenesis and disease progression of sepsis.
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Affiliation(s)
- Liuqing Yang
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Anesthesiology, Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Sugery, Wuhan, China
- Department of Anesthesiology, Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, China
| | - Rui Xuan
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Anesthesiology, Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Sugery, Wuhan, China
- Department of Anesthesiology, Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, China
| | - Dawei Xu
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Anesthesiology, Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Sugery, Wuhan, China
- Department of Anesthesiology, Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, China
| | - Aming Sang
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Anesthesiology, Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Sugery, Wuhan, China
- Department of Anesthesiology, Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, China
| | - Jing Zhang
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Anesthesiology, Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Sugery, Wuhan, China
- Department of Anesthesiology, Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, China
| | - Yanfang Zhang
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xujun Ye
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xinyi Li
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Department of Anesthesiology, Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Sugery, Wuhan, China
- Department of Anesthesiology, Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, China
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Luo J, Zhang C, Chen D, Chang T, Chen S, Lin Z, Yi C, Tang ZH. Tim-3 pathway dysregulation and targeting in sepsis-induced immunosuppression. Eur J Med Res 2024; 29:583. [PMID: 39696711 PMCID: PMC11656820 DOI: 10.1186/s40001-024-02203-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 12/05/2024] [Indexed: 12/20/2024] Open
Abstract
Sepsis is a major medical problem which causes millions of deaths worldwide every year. The host immune response in sepsis is characterized by acute inflammation and a simultaneous state of immunosuppression. In the later stage of sepsis, immunosuppression is a crucial factor that increases the susceptibility of septic patients to secondary infection and mortality. It is characterized by T cell exhaustion, excessive production of anti-inflammatory cytokines, hyperproliferation of immune suppressor cells and aberrant expression of immune checkpoint molecules. T cell immunoglobulin and mucin domain 3 (Tim-3), an immune checkpoint molecule, is found on the surface of various cells, including macrophages, NK cells, NKT cells, and T cells. There are four different ligands for Tim-3, and accumulating evidence indicates that Tim-3 and its ligands play a crucial role in regulating immune cell dysfunction during sepsis. Anti-Tim-3 antibodies have been applied in the field of cancer immunotherapy and have achieved positive therapeutic effects in some clinical trials. However, the therapeutic efficacy of Tim-3 blockade is still controversial in animal models of sepsis. These challenges highlight the need for a deeper understanding of Tim-3 signaling in sepsis. This review examines the comprehensive effect of Tim-3 signaling in the development of sepsis-induced immunosuppression and the therapeutic efficacy of Tim-3 blockade.
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Affiliation(s)
- Jialiu Luo
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong Zhang
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Deng Chen
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Teding Chang
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shunyao Chen
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiqiang Lin
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengla Yi
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Zhao-Hui Tang
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Xiang G, Li Q, Lian D, Su C, Li X, Deng S, Xie L. FOXO1-mediated autophagy regulation by miR-223 in sepsis-induced immunosuppression. Front Pharmacol 2024; 15:1469286. [PMID: 39439897 PMCID: PMC11493625 DOI: 10.3389/fphar.2024.1469286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/25/2024] [Indexed: 10/25/2024] Open
Abstract
Introduction Immunosuppression is the main cause of the high mortality rate in patients with sepsis. The decrease in the number and dysfunction of CD4+ T lymphocytes is crucial to the immunosuppressed state of sepsis, in turn affecting the development and prognosis of sepsis. Autophagy has been shown to play an important role in the immune imbalance exhibited during sepsis. Methods In this study, we modulate the expression of miR-223 in CD4+ T lymphocytes, via the transfection of a mimic or an inhibitor of miR-223 to establish cell models of miR-223 overexpression and knockdown, respectively. Levels of autophagy were monitored using a double-labeled lentivirus (mRFP-GFP-LC3) and electron microscopy, and western blot analysis was used to estimate the levels of autophagy-related proteins and FOXO1 in the two cell models after co-treatment with lipopolysaccharide (LPS) and siRNA against FOXO1. Results We found that when the expression of miR-223 increased, FOXO1 expression decreased and autophagy decreased; whereas, when FOXO1 expression was inhibited, autophagy decreased significantly in different cell models after LPS induction. Conclusion Thus, this study proved that miR-223 participate in the regulation of LPS-induced autophagy via the regulation of FOXO1 expression in CD4+ T lymphocytes which shed a new light for the diagnosis and treatment of sepsis.
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Affiliation(s)
- Guoan Xiang
- College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China
- Chinese PLA Medical School, Beijing, China
| | - Qi Li
- Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Di Lian
- College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China
| | - Chengcheng Su
- Department of Respiratory and Critical Care Medicine, Pingjin Hospital, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, China
| | - Xin Li
- Department of Emergency, Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shoulong Deng
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, National Health Commission of China (NHC) Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Lixin Xie
- College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China
- Chinese PLA Medical School, Beijing, China
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Shi S, Deng R, Huang R, Zhou S. Bergapten attenuates sepsis-induced acute lung injury in mice by regulating Th17/Treg balance. Inhal Toxicol 2024; 36:421-430. [PMID: 39420573 DOI: 10.1080/08958378.2024.2400479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 08/30/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND The abnormality of the immune system caused by infection is a contributor to the organ dysfunctions associated with sepsis. The balance between Th17/Treg cells is essential for maintaining immune homeostasis. Bergapten is a natural furocoumarin and has been reported to alleviate the Th17/Treg imbalance. Here, we explored the effects of bergapten on the inflammation and immune state in mouse models of sepsis. METHODS The model was established using the cecal ligation and puncture method. Mice were administered 30 mg/kg bergapten. Histological examination, RT-qPCR, enzyme-linked immunosorbent assay, immunoblotting, immunofluorescence, immunohistochemistry, and flow cytometry were used to evaluate the effects of bergapten in vivo. RESULTS Bergapten ameliorated lung damage, reduced lung wet/dry weight ratio, inhibited myeloperoxidase activity, and reduced inflammatory cell infiltration. Bergapten also restrained sepsis-induced inflammation via inhibition of inflammatory cytokines and NF-κB signaling. These effects were accompanied by the restored Th17/Treg balance induced by bergapten. Bergapten decreased the number of Th17 cells and elevated the number of Tregs, and this effect was mediated by the signal transducer and activator of transcription 5 (STAT5)/Forkhead box P3 (Foxp3) and STAT3/retinoid-related orphan receptor-γt (RORγt) pathways. CONCLUSIONS Bergapten exerted anti-inflammatory effects in acute lung injury by improving the Th17/Treg balance, which suggested a potential of bergapten as an immunomodulatory drug treating sepsis-associated diseases.
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Affiliation(s)
- Shanqiu Shi
- Department of Emergency Medicine, Hanzhong Central Hospital, Hanzhong, China
| | - Rui Deng
- Multimodal Therapy Department of Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Renchun Huang
- Department of Emergency Medicine, Hanzhong Central Hospital, Hanzhong, China
| | - Shitai Zhou
- Department of Emergency Medicine, Hanzhong Central Hospital, Hanzhong, China
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Zhang S, Shan J, Jie Y, Zhang X, Zhu M, Shen J, Mao K, Chen W, Wang Y, Wen Y. Inhibition of PI3K p110δ rebalanced Th17/Treg and reduced macrophages pyroptosis in LPS-induced sepsis. Mol Immunol 2024; 170:110-118. [PMID: 38653076 DOI: 10.1016/j.molimm.2024.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 03/13/2024] [Accepted: 04/09/2024] [Indexed: 04/25/2024]
Abstract
Sepsis is a systemic inflammatory response syndrome caused by trauma or infection, which can lead to multiple organ dysfunction. In severe cases, sepsis can also progress to septic shock and even death. Effective treatments for sepsis are still under development. This study aimed to determine if targeting the PI3K/Akt signaling with CAL-101, a PI3K p110δ inhibitor, could alleviate lipopolysaccharide (LPS)-induced sepsis and contribute to immune tolerance. Our findings indicated that CAL-101 treatment improved survival rates and alleviated the progression of LPS-induced sepsis. Compared to antibiotics, CAL-101 not only restored the Th17/regulatory T cells (Treg) balance but also enhanced Treg cell function. Additionally, CAL-101 promoted type 2 macrophage (M2) polarization, inhibited TNF-α secretion, and increased IL-10 secretion. Moreover, CAL-101 treatment reduced pyroptosis in peritoneal macrophages by inhibiting caspase-1/gasdermin D (GSDMD) activation. This study provides a mechanistic basis for future clinical exploration of targeted therapeutics and immunomodulatory strategies in the treatment of sepsis.
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Affiliation(s)
- Shiyun Zhang
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China
| | - Jiajia Shan
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China
| | - Yiyang Jie
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China
| | - Xian Zhang
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China
| | - Minyi Zhu
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China
| | - Jingwen Shen
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China
| | - Kefan Mao
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China
| | - Wenhao Chen
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China
| | - Yong Wang
- State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China.
| | - Yanting Wen
- State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, The Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China.
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Wu Z, Liu X, Huang W, Chen J, Li S, Chao J, Xie J, Liu L, Yang Y, Wu X, Qiu H. CIRP increases Foxp3 + regulatory T cells and inhibits development of Th17 cells by enhancing TLR4-IL-2 signaling in the late phase of sepsis. Int Immunopharmacol 2024; 132:111924. [PMID: 38531201 DOI: 10.1016/j.intimp.2024.111924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 03/14/2024] [Accepted: 03/21/2024] [Indexed: 03/28/2024]
Abstract
BACKGROUND T helper (Th) cell imbalances have been associated with the pathophysiology of sepsis, including the Th1/Th2 and Th17/T regulatory cells (Treg) paradigms. Cold-inducible RNA-binding protein (CIRP), a novel damage-associated molecular pattern (DAMP) was reported that could induce T cell activation, and skew CD4+ T cells towards a Th1 profile. However, the effect and underlying mechanisms of CIRP on Th17/Treg differentiation in sepsis still remains unknown. METHODS A prospective exploratory study including patients with sepsis was conducted. Blood samples were collected from patients on days 0, 3 and 7 on admission. The serum CIRP and peripheral blood Treg/Th17 percentage was determined by ELISA and flow cytometry. CD4+ T cells from the spleen and lymph nodes of mice with experimental sepsis were collected after treatment with normal saline (NS), recombinant murine CIRP (rmCIRP) and C23 (an antagonist for CIRP-TLR4) at late stage of sepsis. RNA-seq was conducted to reveal the pivotal molecular mechanism of CIRP on Treg/Th17 differentiation. Naïve CD4+ T cell was isolated from the Tlr4 null and wildtype mice in the presence or absence rmCIRP and C23 to confirmed above findings. RESULTS A total of 19 patients with sepsis finally completed the study. Serum CIRP levels remained high in the majority of patients up to 1 week after admittance was closely associated with high Treg/Th17 ratio of peripheral blood and poor outcome. A univariate logistic analysis demonstrated that higher CIRP concentration at Day 7 is an independent risk factor for Treg/Th17 ratio increasing. CIRP promotes Treg development and suppresses Th17 differentiation was found both in vivo and in vitro. Pretreated with C23 not only alleviated the majority of negative effect of CIRP on Th17 differentiation, but also inhibited Treg differentiation, to some extent. Tlr4 deficiency could abolish almost all downstream effects of rmCIRP. Furthermore, IL-2 is proved a key downstream molecules of the effect CIRP, which also could amplify the activated CD4+ T lymphocytes. CONCLUSIONS Persistent high circulating CIRP level may lead to Treg/Th17 ratio elevated through TLR4 and subsequent active IL-2 signaling which contribute to immunosuppression during late phases of sepsis.
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Affiliation(s)
- Zongsheng Wu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Xu Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Wei Huang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Jing Chen
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Songli Li
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Jie Chao
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Jianfeng Xie
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Ling Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Yi Yang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Xiaojing Wu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
| | - Haibo Qiu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
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Wu Y, Wu G, Li M, Chang Y, Yu M, Meng Y, Wan X. Prediction of Th17/Treg cell balance on length of stay in intensive care units of patients with sepsis. JOURNAL OF INTENSIVE MEDICINE 2024; 4:240-246. [PMID: 38681793 PMCID: PMC11043633 DOI: 10.1016/j.jointm.2023.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 09/17/2023] [Accepted: 09/27/2023] [Indexed: 05/01/2024]
Abstract
Background Prolonged length of stay (LOS) of sepsis can drain a hospital's material and human resources. This study investigated the correlations between T helper type 17 (Th17) and regulatory T (Treg) balance with LOS in sepsis. Methods A prospective clinical observational study was designed in Changhai Hospital affiliated to Naval Medical University in Shanghai, China, from January to October 2020. The patients diagnosed with sepsis and who met the inclusion and exclusion criteria were recruited and whether the levels of cytokines, procalcitonin, subtypes, and biomarkers of T cells in the peripheral blood were detected. We analyzed the correlation between these and LOS. Results Sixty septic patients were classified into two groups according to whether their intensive care unit (ICU) stay exceeded 14 days. The patients with LOS ≥14 days were older ([72.6±7.5] years vs. [63.3±10.4] years, P=0.015) and had higher Sequential Organ Failure Assessment (SOFA) (median [interquartile range]: 6.5 [5.0-11.0] vs. 4.0 [3.0-6.0], P=0.001) and higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores (16.0 [13.0-21.0] vs. 8.5 [7.0-14.0], P=0.001). There was no difference in other demographic characteristics and cytokines, interleukin-6, tumor necrosis factor-α, and interleukin-10 between the two groups. The Th17/Treg ratio of sepsis with LOS <14 days was considerably lower (0.48 [0.38-0.56] vs. 0.69 [0.51-0.98], P=0.001). For patients with LOS ≥14 days, the area under the receiver operating characteristic curve for the Th17/Treg ratio was 0.766. It improved to 0.840 and 0.850 when combined with the SOFA and APACHE II scores, respectively. Conclusions The Th17/Treg ratio was proportional to septic severity and can be used as a potential predictor of ICU stay in sepsis, presenting a new option for ICU practitioners to better care for patients with sepsis.
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Affiliation(s)
- Yu Wu
- Department of Intensive Care Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
- Department of Anesthesiology, Bethune International Peace Hospital, Shijiazhuang, Hebei, China
| | - Guosheng Wu
- Department of Burns, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Minyu Li
- Department of Special Needs Clinic, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yongqing Chang
- Department of Intensive Care Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Miao Yu
- Department of Intensive Care Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yan Meng
- Department of Intensive Care Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xiaojian Wan
- Department of Intensive Care Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
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Liu X, Chen L, Peng W, Deng H, Ni H, Tong H, Hu H, Wang S, Qian J, Liang A, Chen K. Th17/Treg balance: the bloom and wane in the pathophysiology of sepsis. Front Immunol 2024; 15:1356869. [PMID: 38558800 PMCID: PMC10978743 DOI: 10.3389/fimmu.2024.1356869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 02/20/2024] [Indexed: 04/04/2024] Open
Abstract
Sepsis is a multi-organ dysfunction characterized by an unregulated host response to infection. It is associated with high morbidity, rapid disease progression, and high mortality. Current therapies mainly focus on symptomatic treatment, such as blood volume supplementation and antibiotic use, but their effectiveness is limited. Th17/Treg balance, based on its inflammatory property, plays a crucial role in determining the direction of the inflammatory response and the regression of organ damage in sepsis patients. This review provides a summary of the changes in T-helper (Th) 17 cell and regulatory T (Treg) cell differentiation and function during sepsis, the heterogeneity of Th17/Treg balance in the inflammatory response, and the relationship between Th17/Treg balance and organ damage. Th17/Treg balance exerts significant control over the bloom and wanes in host inflammatory response throughout sepsis.
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Affiliation(s)
- Xinyong Liu
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Longwang Chen
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei Peng
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hongsheng Deng
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hongying Ni
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hongjie Tong
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hangbo Hu
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Shengchao Wang
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jin Qian
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Andong Liang
- Nursing Faculty, School of Medicine, Jinhua Polytechnic, Jinhua, China
| | - Kun Chen
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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10
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Paterson CW, Fay KT, Chen CW, Klingensmith NJ, Gutierrez MB, Liang Z, Coopersmith CM, Ford ML. CTLA-4 Checkpoint Inhibition Improves Sepsis Survival in Alcohol-Exposed Mice. Immunohorizons 2024; 8:74-88. [PMID: 38226924 PMCID: PMC10835704 DOI: 10.4049/immunohorizons.2300060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 12/21/2023] [Indexed: 01/17/2024] Open
Abstract
Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population.
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Affiliation(s)
- Cameron W. Paterson
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
- Lieutenant, Medical Corps, Naval Reserve Officer Training Corp, United States Navy, Atlanta, GA
| | - Katherine T. Fay
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Ching-Wen Chen
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Nathan J. Klingensmith
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Melissa B. Gutierrez
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Zhe Liang
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Craig M. Coopersmith
- Department of Surgery, Emory Critical Care Center, Emory University School of Medicine, Atlanta GA
| | - Mandy L. Ford
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta GA
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11
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Zhu Y, Cai W, Zheng Y, Zhang W, Wang B, Kang Y. BIOINFORMATICS APPLICATIONS UNDER CONDITION CONTROL: HIGH DIAGNOSTIC VALUE OF DDX47 IN REAL MEDICAL SETTINGS. Shock 2024; 61:97-104. [PMID: 37553903 PMCID: PMC11841733 DOI: 10.1097/shk.0000000000002199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 07/28/2023] [Indexed: 08/10/2023]
Abstract
ABSTRACT Sepsis is an organ dysfunction caused by a dysregulated host response to infection and remains an ongoing threat to human health worldwide. Septic shock is the most severe subset of sepsis as characterized by abnormalities in cells, circulation, and metabolism. As a time-dependent condition, early recognition allowing appropriate therapeutic measures to be started in a timely manner becomes the most effective way to improve prognosis. However, because of the lack of a criterion standard, most diagnoses merely rely on medical history, empirical diagnosis, and blood culture results. Gene expression profiles have specific diagnostic value, as they reflect a subjective host response to pathogens. We propose a method, Condition Control based on Real-life Medical Scenarios, to control for factors in realistic medical scenarios. Restricted variables are used as much as possible to identify unique differential genes and progressively test their diagnostic value by relaxing restrictions. In total, three data sets were included in the study; the first two data sets were from the Gene Expression Omnibus database, and the third involved patients who were diagnosed with sepsis or septic shock within 7 days of admission to the intensive care unit at West China Hospital of Sichuan University from 2020 to 2021. DDX47 showed preferable diagnostic value in various scenarios, especially in patients with common infections or sepsis and septic shock. Here we also show that hub genes may regulate immune function and immune cell counts through the interaction of different apoptotic pathways and immune checkpoints based on the high correlation. DDX47 is closely associated with B cells according to single-cell sequencing results.
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Affiliation(s)
- Yukun Zhu
- Department of Critical Care Medicine, West China Hospital, Sichuan University and Institute of Critical Care Medicine, Chengdu, Sichuan Province, China
| | - Wei Cai
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ying Zheng
- Abdominal Oncology Ward, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Wei Zhang
- Department of Critical Care Medicine, West China Hospital, Sichuan University and Institute of Critical Care Medicine, Chengdu, Sichuan Province, China
| | - Bo Wang
- Department of Critical Care Medicine, West China Hospital, Sichuan University and Institute of Critical Care Medicine, Chengdu, Sichuan Province, China
| | - Yan Kang
- Department of Critical Care Medicine, West China Hospital, Sichuan University and Institute of Critical Care Medicine, Chengdu, Sichuan Province, China
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12
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Cao M, Wang G, Xie J. Immune dysregulation in sepsis: experiences, lessons and perspectives. Cell Death Discov 2023; 9:465. [PMID: 38114466 PMCID: PMC10730904 DOI: 10.1038/s41420-023-01766-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/21/2023] Open
Abstract
Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host responses to infection. Not only does sepsis pose a serious hazard to human health, but it also imposes a substantial economic burden on the healthcare system. The cornerstones of current treatment for sepsis remain source control, fluid resuscitation, and rapid administration of antibiotics, etc. To date, no drugs have been approved for treating sepsis, and most clinical trials of potential therapies have failed to reduce mortality. The immune response caused by the pathogen is complex, resulting in a dysregulated innate and adaptive immune response that, if not promptly controlled, can lead to excessive inflammation, immunosuppression, and failure to re-establish immune homeostasis. The impaired immune response in patients with sepsis and the potential immunotherapy to modulate the immune response causing excessive inflammation or enhancing immunity suggest the importance of demonstrating individualized therapy. Here, we review the immune dysfunction caused by sepsis, where immune cell production, effector cell function, and survival are directly affected during sepsis. In addition, we discuss potential immunotherapy in septic patients and highlight the need for precise treatment according to clinical and immune stratification.
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Affiliation(s)
- Min Cao
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Guozheng Wang
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, L69 7BE, UK
- Coagulation, Liverpool University Hospitals NHS Foundation Trust, Liverpool, L7 8XP, UK
| | - Jianfeng Xie
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
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13
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Dreschers S, Platen C, Oppermann L, Doughty C, Ludwig A, Babendreyer A, Orlikowsky TW. EGF-Receptor against Amphiregulin (AREG) Influences Costimulatory Molecules on Monocytes and T Cells and Modulates T-Cell Responses. J Immunol Res 2023; 2023:8883045. [PMID: 38046264 PMCID: PMC10691888 DOI: 10.1155/2023/8883045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/24/2023] [Accepted: 11/02/2023] [Indexed: 12/05/2023] Open
Abstract
Amphiregulin (AREG) is a ligand of the epidermal growth factor receptor (EGFR) and has been shown to regulate the phagocytosis-induced cell death of monocytes in peripheral blood. AREG-dependent apoptotic signaling engages factors of the intrinsic and extrinsic apoptotic pathway, such as BCL-2, BCL-XL, and death ligand/receptor CD95/CD95L. Here, we tested the hypothesis that AREG influences costimulatory monocyte functions, which are crucial for T-cell responses. We found a stronger expression of AREG and EGFR in monocytes compared to lymphocytes. As a novel function of AREG, we observed reduced T-cell proliferation following polyclonal T-cell stimulation with OKT3. This reduction of proliferation occurred in the presence of monocytes as well as in their absence, monocyte signaling being replaced by crosslinking of OKT3. Increasing concentrations of AREG down-modulated the concentration of costimulatory B7 molecules (CD80/CD86) and HLA-DR on monocytes. In proliferation assays, CD28 expression on T cells was down-modulated on the application of OKT3 but unaltered by AREG. LcK activation, following OKT3-stimulation, was reduced in T cells that had been coincubated with AREG. The effects of AREG on T-cell phenotypes were also present when monocytes were depleted and OKT3 was crosslinked. The rearranged expression of immunological synapse proteins was accompanied by an alteration of T-cell polarization. Although the proportion of regulatory T cells was not shifted by AREG, IL-17-expressing T cells were significantly enhanced, with a bias toward TH1-polarization. Taken together, these results suggest that AREG acts as an immunoregulatory molecule at the interface between antigen-presenting cells and T cells.
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Affiliation(s)
- Stephan Dreschers
- Department of Neonatology, University Children's Hospital, Aachen, Germany
| | - Christopher Platen
- Department of Neonatology, University Children's Hospital, Aachen, Germany
| | - Louise Oppermann
- Department of Neonatology, University Children's Hospital, Aachen, Germany
| | - Caitlin Doughty
- Department of Neonatology, University Children's Hospital, Aachen, Germany
| | - Andreas Ludwig
- Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Aaron Babendreyer
- Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany
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14
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Jin H, Wei W, Zhao Y, Ma A, Sun K, Lin X, Liu Q, Shou S, Zhang Y. The roles of interleukin-17A in risk stratification and prognosis of patients with sepsis-associated acute kidney injury. Kidney Res Clin Pract 2023; 42:742-750. [PMID: 37448288 DOI: 10.23876/j.krcp.22.063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 07/01/2022] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND The aim of this study was to evaluate the roles of interleukin (IL)-17A in risk stratification and prognosis of patients with sepsis-associated acute kidney injury (SAKI). METHODS We enrolled 146 sepsis patients (84 non-SAKI and 62 SAKI patients) admitted to the emergency department from November 2020 to November 2021. Patients with SAKI were differentiated based on the severity of acute kidney injury. All clinical parameters were evaluated upon admission before administering antibiotic treatment. Inflammatory cytokines were assessed using flow cytometry and the Pylon 3D automated immunoassay system (ET Healthcare). In addition, a receiver operating characteristic (ROC) curve was utilized to determine the prognostic values of IL-17A in SAKI. RESULTS The levels of creatinine, IL-2, IL-4, IL-6, IL-17A, tumor necrosis factor alpha, C-reactive protein, and procalcitonin (PCT) were significantly higher in the SAKI group than in the non-SAKI group (p < 0.05). The level of IL-17A revealed significant differences among stages 1, 2, and 3 in SAKI patients (p < 0.05). The mean levels of PCT, IL-4, and IL-17A were significantly higher in the non-survival group than in the survival group in SAKI patients (p < 0.05). In addition, the area under the ROC curve of IL-17A was 0.811. Moreover, the IL-17A cutoff for differentiating survivors from non-survivors was 4.7 pg/mL, of which the sensitivity and specificity were 77.4% and 71.0%, respectively. CONCLUSION Elevated levels of IL-17A could predict that SAKI patients are significantly prone to worsening kidney injury with higher mortality. The usefulness of IL-17A in treating SAKI requires further research.
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Affiliation(s)
- Heng Jin
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Wei Wei
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Yibo Zhao
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Ai Ma
- Department of Clinical Laboratory, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Keke Sun
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaoxi Lin
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Qihui Liu
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Songtao Shou
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Yan Zhang
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin, China
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15
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Pei F, Yao RQ, Ren C, Bahrami S, Billiar TR, Chaudry IH, Chen DC, Chen XL, Cui N, Fang XM, Kang Y, Li WQ, Li WX, Liang HP, Lin HY, Liu KX, Lu B, Lu ZQ, Maegele M, Peng TQ, Shang Y, Su L, Sun BW, Wang CS, Wang J, Wang JH, Wang P, Xie JF, Xie LX, Zhang LN, Zingarelli B, Guan XD, Wu JF, Yao YM. Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression. Mil Med Res 2022; 9:74. [PMID: 36567402 PMCID: PMC9790819 DOI: 10.1186/s40779-022-00430-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 11/14/2022] [Indexed: 12/27/2022] Open
Abstract
Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.
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Affiliation(s)
- Fei Pei
- Department of Critical Care Medicine, the First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan Er Road, Yuexiu District, Guangzhou, 510080, Guangdong, China
| | - Ren-Qi Yao
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China.,Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Chao Ren
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Soheyl Bahrami
- Ludwig-Boltzmann Institute for Experimental and Clinical Traumatology, 1200, Vienna, Austria
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Irshad H Chaudry
- Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - De-Chang Chen
- Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Xu-Lin Chen
- Department of Burns, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Na Cui
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Xiang-Ming Fang
- Department of Anesthesiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 31003, China
| | - Yan Kang
- Department of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Wei-Qin Li
- Department of Critical Care Medicine, General Hospital of Eastern Theater Command of Chinese PLA, Nanjing, 210002, China
| | - Wen-Xiong Li
- Department of Surgical Intensive Critical Unit, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China
| | - Hua-Ping Liang
- State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Hong-Yuan Lin
- Department of Critical Care Medicine, Fourth Medical Center of the Chinese PLA General Hospital, Beijing, 100048, China
| | - Ke-Xuan Liu
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ben Lu
- Department of Critical Care Medicine and Hematology, the Third Xiangya Hospital, Central South University, Changsha, 410000, China
| | - Zhong-Qiu Lu
- Emergency Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Marc Maegele
- Department of Traumatology and Orthopedic Surgery, University Witten-Herdecke, 51109, Cologne, Germany
| | - Tian-Qing Peng
- Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, London, ON, N6A 4G4, Canada
| | - You Shang
- Department of Critical Care Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lei Su
- Department of Intensive Care Unit, General Hospital of Southern Theater Command of Chinese PLA, Guangzhou, 510030, China
| | - Bing-Wei Sun
- Department of Burns and Plastic Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, China
| | - Chang-Song Wang
- Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jian Wang
- Children's Hospital of Soochow University, Pediatric Research Institute of Soochow University, Suzhou, 215123, China
| | - Jiang-Huai Wang
- Department of Academic Surgery, University College Cork, Cork University Hospital, Cork, T12 E8YV, Ireland
| | - Ping Wang
- Center for Immunology and Inflammation, the Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Jian-Feng Xie
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Li-Xin Xie
- Department of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, 100853, China
| | - Li-Na Zhang
- Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Basilia Zingarelli
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 41073, USA
| | - Xiang-Dong Guan
- Department of Critical Care Medicine, the First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan Er Road, Yuexiu District, Guangzhou, 510080, Guangdong, China.
| | - Jian-Feng Wu
- Department of Critical Care Medicine, the First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan Er Road, Yuexiu District, Guangzhou, 510080, Guangdong, China. .,Guangdong Clinical Research Center for Critical Care Medicine, Guangzhou, 510080, China.
| | - Yong-Ming Yao
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China.
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16
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Klingensmith NJ, Fay KT, Swift DA, Bazzano JM, Lyons JD, Chen CW, Meng M, Ramonell KM, Liang Z, Burd EM, Parkos CA, Ford ML, Coopersmith CM. Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis. JCI Insight 2022; 7:156255. [PMID: 35819838 PMCID: PMC9462501 DOI: 10.1172/jci.insight.156255] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 07/07/2022] [Indexed: 11/28/2022] Open
Abstract
Expression of the tight junction–associated protein junctional adhesion molecule-A (JAM-A) is increased in sepsis, although the significance of this is unknown. Here, we show that septic JAM-A –/– mice have increased gut permeability, yet paradoxically have decreased bacteremia and systemic TNF and IL-1β expression. Survival is improved in JAM-A–/– mice. However, intestine-specific JAM-A–/– deletion does not alter mortality, suggesting that the mortality benefit conferred in mice lacking JAM-A is independent of the intestine. Septic JAM-A–/– mice have increased numbers of splenic CD44hiCD4+ T cells, decreased frequency of TNF+CD4+ cells, and elevated frequency of IL-2+CD4+ cells. Septic JAM-A–/– mice have increased numbers of B cells in mesenteric lymph nodes with elevated serum IgA and intraepithelial lymphocyte IgA production. JAM-A–/– × RAG–/– mice have improved survival compared with RAG–/– mice and identical mortality as WT mice. Gut neutrophil infiltration and neutrophil phagocytosis are increased in JAM-A–/– mice, while septic JAM-A–/– mice depleted of neutrophils lose their survival advantage. Therefore, increased bacterial clearance via neutrophils and an altered systemic inflammatory response with increased opsonizing IgA produced through the adaptive immune system results in improved survival in septic JAM-A–/– mice. JAM-A may be a therapeutic target in sepsis via immune mechanisms not related to its role in permeability.
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Affiliation(s)
- Nathan J Klingensmith
- Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America
| | - Katherine T Fay
- Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America
| | - David A Swift
- Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, United States of America
| | - Julia Mr Bazzano
- Department of Surgery and Emory Critical Care Center, Emory Univerisity School of Medicine, Atlanta, United States of America
| | - John D Lyons
- Department of Surgery and Emory Critical Care Center, Emory Univerisity School of Medicine, Atlanta, United States of America
| | - Ching-Wen Chen
- Department of Surgery and Emory Critical Care Center, Emory Univerisity School of Medicine, Atlanta, United States of America
| | - Mei Meng
- Department of Surgery and Emory Critical Care Center, Emory Univerisity School of Medicine, Atlanta, United States of America
| | - Kimberly M Ramonell
- Department of Surgery and Emory Critical Care Center, Emory Univerisity School of Medicine, Atlanta, United States of America
| | - Zhe Liang
- Department of Surgery and Emory Critical Care Center, Emory Univerisity School of Medicine, Atlanta, United States of America
| | - Eileen M Burd
- Department of Pathology and Laboratory Medicine, Emory Univerisity School of Medicine, Atlanta, United States of America
| | - Charles A Parkos
- Department of Pathology, University of Michigan, Ann Arbor, United States of America
| | - Mandy L Ford
- Department of Surgery and Emory Critical Care Center, Emory Univerisity School of Medicine, Atlanta, United States of America
| | - Craig M Coopersmith
- Department of Surgery and Emory Critical Care Center, Emory Univerisity School of Medicine, Atlanta, United States of America
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17
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Marashian SM, Hashemian M, Pourabdollah M, Nasseri M, Mahmoudian S, Reinhart F, Eslaminejad A. Photobiomodulation Improves Serum Cytokine Response in Mild to Moderate COVID-19: The First Randomized, Double-Blind, Placebo Controlled, Pilot Study. Front Immunol 2022; 13:929837. [PMID: 35874678 PMCID: PMC9304695 DOI: 10.3389/fimmu.2022.929837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/20/2022] [Indexed: 01/03/2023] Open
Abstract
BackgroundBecause the major event in COVID-19 is the release of pre- and inflammatory cytokines, finding a reliable therapeutic strategy to inhibit this release, help patients manage organ damage and avoid ICU admission or severe disease progression is of paramount importance. Photobiomodulation (PBM), based on numerous studies, may help in this regard, and the present study sought to evaluate the effects of said technology on cytokine reduction.MethodsThis study was conducted in the 2nd half of 2021. The current study included 52 mild-to-moderately ill COVID-19, hospitalized patients. They were divided in two groups: a Placebo group and a PBM group, treated with PBM (620-635 nm light via 8 LEDs that provide an energy density of 45.40 J/cm2 and a power density of 0.12 W/cm2), twice daily for three days, along with classical approved treatment. 28 patients were in Placebo group and 24 in PBM group. In both groups, blood samples were taken four times in three days and serum IL-6, IL-8, IL-10, and TNF-α levels were determined.ResultsDuring the study period, in PBM group, there was a significant decrease in serum levels of IL-6 (-82.5% +/- 4, P<0.001), IL-8 (-54.4% ± 8, P<0.001), and TNF-α (-82.4% ± 8, P<0.001), although we did not detect a significant change in IL-10 during the study. The IL-6/IL-10 Ratio also improved in PBM group. The Placebo group showed no decrease or even an increase in these parameters. There were no reported complications or sequelae due to PBM therapy throughout the study.ConclusionThe major cytokines in COVID-19 pathophysiology, including IL-6, IL-8, and TNF-α, responded positively to PBM therapy and opened a new window for inhibiting and managing a cytokine storm within only 3-10 days.
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Affiliation(s)
- Seyed Mehran Marashian
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Hashemian
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mihan Pourabdollah
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mansour Nasseri
- Department of Immunology, School of Public Health, University of Medical Sciences, Tehran, Iran
| | - Saeed Mahmoudian
- National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Florian Reinhart
- Medical Research & Innovation Department, Medical and Biomedical Consultancy Office “Innolys”, Illkirch-Graffenstaden, France
- *Correspondence: Florian Reinhart,
| | - Alireza Eslaminejad
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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18
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Azaiz MB, Jemaa AB, Sellami W, Romdhani C, Ouslati R, Gharsallah H, Ghazouani E, Ferjani M. Deciphering the balance of IL-6/IL-10 cytokines in severe to critical COVID-19 patients. Immunobiology 2022; 227:152236. [PMID: 35691133 PMCID: PMC9173832 DOI: 10.1016/j.imbio.2022.152236] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 05/29/2022] [Accepted: 06/06/2022] [Indexed: 12/22/2022]
Abstract
The severity of COVID-19 is largely determined by the inflammatory response, a “Cytokine storm,” that involves both pro- and anti-inflammatory cytokines. In the current study we investigated the balance of pro- and anti-inflammatory status as represented by the levels of IL-6/IL-10 in severe to critical COVID-19 patients. 66 confirmed COVID-19 patients admitted to the ICU were categorized into groups according to the mortality and respiratory failure. Data were collected retrospectively in ICU, including a peripheral immune cells and infection-related biomarker CRP. The measurements of cytokine levels were performed by Immulite analyzer for IL-6 and ELISA sandwich for IL-10. In addition, longitudinal measurement of IL-6 was performed during 5 days post admission. Longitudinal assays showed that IL-6 was sustained at a medium level within 5 days post admission in severe cases who survived or not requiring mechanical ventilation, whereas it was sustained at high levels throughout the disease course in either deceased cases or who developed respiratory failure. The ratio of IL-6/lymphocytes was positively correlated with the risk of mortality, while IL-10/lymphocytes ratio could predict respiratory failure in ICU. IL-6/IL-10 profiling revealed that deceased patients have different magnitudes of both IL-6 and IL-10 cytokine release. Notably, excessive levels of IL-6 concomitant with high levels of IL-10 were more common in diseased COVID-19 patients. Taking into account the IL-6/IL-10 profiling may help clinicians to identify the right time of anti-inflammation treatment and select patients who will respond to anti-cytokine therapies and maintain an adequate inflammatory response for SARS-CoV-2 clearance.
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Affiliation(s)
- Mouna Ben Azaiz
- Department of Immunology, Military Hospital of Tunis, Montfleury - 1008, Tunis, Tunisia; Unit IMEC-Immunology Microbiology Environmental and Carcinogenesis, Faculty of Science of Bizerte, Tunisia; Faculty of Medicine, University Tunis El Manar, Tunis, Tunisia.
| | - Awatef Ben Jemaa
- Unit IMEC-Immunology Microbiology Environmental and Carcinogenesis, Faculty of Science of Bizerte, Tunisia; Department of Biology, Faculty of Science of Gafsa, University of Gafsa, Gafsa, Tunisia
| | - Walid Sellami
- Department of Intensive Care, Military Hospital of Tunis, Mont fleury - 1008, Tunis, Tunisia; Faculty of Medicine, University Tunis El Manar, Tunis, Tunisia
| | - Chihebeddine Romdhani
- Department of Intensive Care, Military Hospital of Tunis, Mont fleury - 1008, Tunis, Tunisia; Research Unit 17 DN05, Military Hospital of Tunis, Montfleury - 1008, Tunis, Tunisia
| | - Ridha Ouslati
- Unit IMEC-Immunology Microbiology Environmental and Carcinogenesis, Faculty of Science of Bizerte, Tunisia
| | - Hedi Gharsallah
- Department of Intensive Care, Military Hospital of Tunis, Mont fleury - 1008, Tunis, Tunisia; Research Unit 17 DN05, Military Hospital of Tunis, Montfleury - 1008, Tunis, Tunisia; Faculty of Medicine, University Tunis El Manar, Tunis, Tunisia
| | - Ezzedine Ghazouani
- Department of Immunology, Military Hospital of Tunis, Montfleury - 1008, Tunis, Tunisia
| | - Mustapha Ferjani
- Department of Intensive Care, Military Hospital of Tunis, Mont fleury - 1008, Tunis, Tunisia; Faculty of Medicine, University Tunis El Manar, Tunis, Tunisia
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19
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Yao RQ, Ren C, Zheng LY, Xia ZF, Yao YM. Advances in Immune Monitoring Approaches for Sepsis-Induced Immunosuppression. Front Immunol 2022; 13:891024. [PMID: 35619710 PMCID: PMC9127053 DOI: 10.3389/fimmu.2022.891024] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 03/29/2022] [Indexed: 12/29/2022] Open
Abstract
Sepsis represents a life-threatening organ dysfunction due to an aberrant host response. Of note is that majority of patients have experienced a severe immune depression during and after sepsis, which is significantly correlated with the occurrence of nosocomial infection and higher risk of in-hospital death. Nevertheless, the clinical sign of sepsis-induced immune paralysis remains highly indetectable and ambiguous. Given that, specific yet robust biomarkers for monitoring the immune functional status of septic patients are of prominent significance in clinical practice. In turn, the stratification of a subgroup of septic patients with an immunosuppressive state will greatly contribute to the implementation of personalized adjuvant immunotherapy. In this review, we comprehensively summarize the mechanism of sepsis-associated immunosuppression at the cellular level and highlight the recent advances in immune monitoring approaches targeting the functional status of both innate and adaptive immune responses.
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Affiliation(s)
- Ren-Qi Yao
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.,Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chao Ren
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.,Department of Pulmonary and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Li-Yu Zheng
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Zhao-Fan Xia
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yong-Ming Yao
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
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20
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Th17 cell plasticity towards a T-bet-dependent Th1 phenotype is required for bacterial control in Staphylococcus aureus infection. PLoS Pathog 2022; 18:e1010430. [PMID: 35446923 PMCID: PMC9064098 DOI: 10.1371/journal.ppat.1010430] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/03/2022] [Accepted: 03/09/2022] [Indexed: 12/29/2022] Open
Abstract
Staphylococcus aureus is frequently detected in patients with sepsis and thus represents a major health burden worldwide. CD4+ T helper cells are involved in the immune response to S. aureus by supporting antibody production and phagocytosis. In particular, Th1 and Th17 cells secreting IFN-γ and IL-17A, are involved in the control of systemic S. aureus infections in humans and mice. To investigate the role of T cells in severe S. aureus infections, we established a mouse sepsis model in which the kidney was identified to be the organ with the highest bacterial load and abundance of Th17 cells. In this model, IL-17A but not IFN-γ was required for bacterial control. Using Il17aCre × R26YFP mice we could show that Th17 fate cells produce Th17 and Th1 cytokines, indicating a high degree of Th17 cell plasticity. Single cell RNA-sequencing of renal Th17 fate cells uncovered their heterogeneity and identified a cluster with a Th1 expression profile within the Th17 cell population, which was absent in mice with T-bet/Tbx21-deficiency in Th17 cells (Il17aCre x R26eYFP x Tbx21-flox). Blocking Th17 to Th1 transdifferentiation in Th17 fate cells in these mice resulted in increased S. aureus tissue loads. In summary, we highlight the impact of Th17 cells in controlling systemic S. aureus infections and show that T-bet expression by Th17 cells is required for bacterial clearance. While targeting the Th17 cell immune response is an important therapeutic option in autoimmunity, silencing Th17 cells might have detrimental effects in bacterial infections. Staphylococcus aureus is a commensal and opportunistic pathogen that is involved in a variety of diseases such as skin infection, food poisoning, endocarditis or pneumonia and sepsis. In particular, in patients with bacterial sepsis, S. aureus causes a high mortality. Despite progress in medical treatment in general, the survival rates of S. aureus sepsis did not improve in the last decades. The interaction between adaptive immune system and this pathogen is a topic of great interest. Infection of mice with S. aureus revealed the highest bacterial load and abundance of Th17 cells in the kidney. We could show prominent T-bet-dependent transdifferentiation of Th17 cells to highly effective anti-bacterial Th1 phenotypes in the kidney. Thus, T-bet is essential for the Th17 to Th1 transdifferentiation which is required for the control of bacterial infections. Targeting the plasticity of pro-inflammatory T cell subset is a promising therapeutic strategy to silence detrimental T cells in autoimmunity while augmenting anti-bacterial T cells in infection.
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21
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Jin B, Cao D, Yang N, Wang L, Li R, Liu X, Gong P. Early High-dose Continuous Veno-venous Hemofiltration Alleviates the Alterations of CD4+ T Lymphocyte Subsets in Septic Patients Combined with Acute Kidney Injury. Artif Organs 2022; 46:1415-1424. [PMID: 35132659 DOI: 10.1111/aor.14199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 01/05/2022] [Accepted: 02/02/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND This study aims to determine whether early high-dose continuous venous-venous hemofiltration (CVVH) alleviates the alterations in CD4+ T lymphocyte subsets in septic patients combined with acute kidney injury. METHODS Enrolled septic patients combined with acute kidney injury were randomized into CVVH (n = 50) and conventional treatment (non-CVVH, n = 53) groups. Healthy volunteers (n = 21) were enrolled. CVVH was initiated within 12 h of intensive care unit (ICU) admission with the doses of 35 ~ 60 mL/kg/h and maintained for at least 72 h. Th1, Th2, Th17 and Treg were measured by flow cytometry on days 1, 3 and 7 of ICU admission. Sequential organ failure assessment (SOFA) scores were calculated. RESULTS Th1 percentages and Th1/Th2 ratios were lower, and Th2, Th17 and Treg percentages and Th17/Treg ratios were higher in septic patients compared to healthy volunteers. CVVH significantly increased Th1 percentages and Th1/Th2 ratios, and significantly decreased Th2, Th17 and Treg percentages and Th17/Treg ratios compared to non-CVVH. Th1 percentages and Th1/Th2 ratios were negatively correlated with SOFA scores, while Th2, Th17 and Treg percentages and Th17/Treg ratios were positively correlated with SOFA scores. Patients with CVVH had significantly lower SOFA scores on day 7 of ICU admission and a shorter ICU stay compared to those with non-CVVH. CONCLUSIONS Septic patients combined with acute kidney injury exhibit different alterations of CD4+ T lymphocyte subsets. Early high-dose CVVH alleviates the alterations, which may be one of factors associated with improved sepsis severity.
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Affiliation(s)
- Beibei Jin
- Department of Emergency, First Affiliated Hospital of Dalian Medical University, Dalian City, Liaoning Province, China.,Department of Emergency, First Affiliated Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Da Cao
- Department of Emergency, Southeast University Zhongda Hospital, 210009, Jiangsu, China
| | - Ning Yang
- Department of Nephrology, First Affiliated Hospital of Dalian Medical University, Dalian City, Liaoning Province, China
| | - Ling Wang
- Department of Emergency, First Affiliated Hospital of Dalian Medical University, Dalian City, Liaoning Province, China
| | - Ruifang Li
- Department of Emergency, First Affiliated Hospital of Dalian Medical University, Dalian City, Liaoning Province, China
| | - Xiumei Liu
- Department of Intensive Care Medicine, First Affiliated Hospital of Dalian Medical University, Dalian City, Liaoning Province, China
| | - Ping Gong
- Department of Emergency, First Affiliated Hospital of Dalian Medical University, Dalian City, Liaoning Province, China
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22
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Peng Y, Wang X, Yin S, Wang M. A new indicator: The diagnostic value of CD8+T/B lymphocyte ratio in sepsis progression. Int J Immunopathol Pharmacol 2022; 36:3946320221123164. [PMID: 36036157 PMCID: PMC9421217 DOI: 10.1177/03946320221123164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective To reveal the value of single lymphocyte subpopulation and their ratios in
the progression of sepsis. Methods From January 2019 to March 2021, 39 sepsis patients, 16 septic shock
patients, and 50 healthy volunteers were recruited in the Second Xiangya
Hospital for this cross-sectional study. The absolute quantitation of CD4+T,
CD8+T, B lymphocytes, and NK cells in peripheral blood were determined by
flow cytometry. SPSS Software was used to analyze the results. Results On the whole, the numbers of lymphocytes in the sepsis group and in the
septic shock group were lower than that in the healthy control group.
Surprisingly, the percentage of CD8+T lymphocytes in the septic shock group
was slightly higher than that in the sepsis group. The percentage of B
lymphocytes in the sepsis group was higher than that in the healthy control
group. The AUC of CD8+T/B was 0.724, with the sensitivity and specificity
being 75.00% and 71.79%, respectively. Conclusion The immune expression pattern of patients with sepsis was not a simple
decrease in the number of lymphocytes. The change in the ratios of
lymphocyte subpopulation might be more meaningful along the development and
progression of sepsis. The ratio of CD8+T/B could be used to diagnose the
progression of sepsis and reduce the misdiagnosis rate to a certain
extent.
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Affiliation(s)
- Yizhi Peng
- Department of Laboratory Medicine, 70566The Second Xiangya Hospitalof Central South University, Changsha, Hunan, China
| | - Xiaofan Wang
- Department of Laboratory Medicine, 70566The Second Xiangya Hospitalof Central South University, Changsha, Hunan, China
| | - Sheng Yin
- Department of Laboratory Medicine, 70566The Second Xiangya Hospitalof Central South University, Changsha, Hunan, China
| | - Min Wang
- Department of Laboratory Medicine, 70566The Second Xiangya Hospitalof Central South University, Changsha, Hunan, China
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23
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Vázquez AC, Arriaga-Pizano L, Ferat-Osorio E. Cellular Markers of Immunosuppression in Sepsis. Arch Med Res 2021; 52:828-835. [PMID: 34702587 DOI: 10.1016/j.arcmed.2021.10.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/27/2021] [Accepted: 10/04/2021] [Indexed: 12/16/2022]
Abstract
Sepsis is a pathological condition frequently caused by invasion of a pathogen and the subsequent unregulated response that threatens the patient's life through diverse organ failure. The incidence of sepsis is increasing, and there is no specific therapy. Despite technological contributions to treat sepsis or increased knowledge of its molecular pathophysiology, mortality remains high, and sepsis is a global health problem. Knowledge of the role of the cells involved in the host response through the synthesis of inflammatory mediators and their different effects on cells, tissues or systems is key to the development of medical treatments that regulate systems involved in such responses to pathogens. This review addresses new insights into the role of cells, their mediators, and the interaction between them that lead to the development of a state of immunosuppression.
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Affiliation(s)
- Arturo Cérbulo Vázquez
- Servicio de Medicina Genómica, Hospital General de México, Dr Eduardo Liceaga, Ciudad de México, México
| | - Lourdes Arriaga-Pizano
- Unidad de Investigación Médica en Inmunoquímica de la Unidad de Investigación en Epidemiología Clínica, Hospital de Especialidades, Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Eduardo Ferat-Osorio
- División de Investigación en Salud, Unidad de Investigación en Epidemiología Clínica, Hospital de Especialidades, Dr. Bernardo Sepúlveda Gutiérrez, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.
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24
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Park SJ, Lee M, Kim D, Oh DH, Prasad KS, Eun S, Lee J. Echinacea purpurea Extract Enhances Natural Killer Cell Activity In Vivo by Upregulating MHC II and Th1-type CD4 + T Cell Responses. J Med Food 2021; 24:1039-1049. [PMID: 34668764 DOI: 10.1089/jmf.2021.k.0064] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
There are a number of factors that cause immune system disruption, including infection caused by foreign antigens and decreased immunity due to excessive exercise, and public interest in improving immunity is growing. In this study, we investigate the immunomodulatory effects of Echinacea purpurea (E) extract in C57BL/6N mice that were exposed to a forced swimming exercise. There were six experimental groups as follows: wild-type, forced swimming exercise control, positive control (red ginseng, 300 mg/kg), and E (50, 100, and 200 mg/kg b.w.) groups. The mice were administered the E extract for 2 weeks. We detected chicoric acid, the active substance of E, through high-performance liquid chromatography and evaluated changes in the following laboratory values in response to forced swimming exercise using flow cytometry and ELISA: the major histocompatibility complex (MHC), CD4+ and CD8+ T cells, Th1 and Th2 cytokines, natural killer (NK) cell activity, and number of leukocytes. Oral E intake increased levels of MHC II, CD4+ T cells, Th1 cytokines, and NK cell activity. In addition, E treatment increased B cell proliferation, leukocyte counts, and immunoglobulin levels. Taken together, these results suggest that the chicoric acid of E can improve immune response by controlling NK cell activity, which may be a useful function for immunomodulation systems.
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Affiliation(s)
- Soo-Jeung Park
- Department of Medical Nutrition, Kyung Hee University, Yongin, Korea
| | - Minhee Lee
- Department of Medical Nutrition, Kyung Hee University, Yongin, Korea
| | - Dakyung Kim
- Department of Medical Nutrition, Kyung Hee University, Yongin, Korea
| | - Dong Hwan Oh
- Department of Medical Nutrition, Kyung Hee University, Yongin, Korea
| | | | - Sangwon Eun
- R&D Division, Daehan Chemtech Co., Ltd., Seoul, Korea
| | - Jeongmin Lee
- Department of Medical Nutrition, Kyung Hee University, Yongin, Korea
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25
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Zhang L, Zhang JP, Liu Y, Wang H, Cheng Y, Wang JH, Zhang WJ, Li ZZ, Guo JR. Plasma Transfusion Promoted Reprogramming CD4 + T Lymphocytes Immune Response in Severe Sepsis Mice Model Through Modulating the Exosome Protein Galectin 9. Cell Transplant 2021; 29:963689720947347. [PMID: 32907380 PMCID: PMC7784505 DOI: 10.1177/0963689720947347] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Sepsis is a life-threatening disease that results in excessive stimulation of the host's immune cells. In the animal study, the purpose was to investigate the roles of fresh frozen plasma (FFP) transfusion in shaping the CD4+ T lymphocytes immune response through modulating the secreted exosome protein Galectin-9 in mice with severe sepsis. By using Western blot analysis, we first identified that the protein Galectin-9 is highly accumulated in the blood plasma of severe sepsis mice, and with transmission electron microscopy (TEM) and protein analysis, we found that Galectin-9 is a secreted exosome protein. Thereafter, we treated the severe sepsis mice with the antibiotic Cefuroxime Axetil; one group of mice received FFP transfusion and the other group of mice received normal saline. Surprisingly, the FFP transfusion reduced the secretion of exosome protein Galectin-9 and there was crosstalking between the exosome protein Galectin-9 and CD4+ T lymphocytes in mice with severe sepsis. Results showed that the proliferation of T helper (Th) cells (Th1 and Th17) was promoted, and regulatory T (Treg) cells' maintenance was inhibited in the sepsis mice after receiving FFP transfusion. Correspondingly, this immune reprogrammed activity shaped the inflammatory cytokine secretion with an increase in the interleukin (IL)-1β, IL-6, and interferon-gamma levels, while it decreased IL-10 levels. Taken together, it was suggested that FFP transfusion promoted reprogramming of CD4+ T lymphocytes' immune response through inhibiting the secretion of exosome protein Galectin-9 in mice with severe sepsis to relieve immunosuppression.
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Affiliation(s)
- Lei Zhang
- Department of Burn Surgery, First Hospital, Jilin University, Changchun, Jilin, P. R. China
| | - Jian-Ping Zhang
- Division of Life Sciences and Medicine, Department of Anesthesiology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P. R. China
| | - Yang Liu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P. R. China
| | - Huan Wang
- Department of Anesthesiology, Shanghai Gongli Hospital, the Second Military Medical University, Shanghai, P. R. China
| | - Yong Cheng
- Department of Anesthesiology, Shanghai Gongli Hospital, the Second Military Medical University, Shanghai, P. R. China
| | - Jin-Huo Wang
- Department of Anesthesiology, Shanghai Gongli Hospital, the Second Military Medical University, Shanghai, P. R. China
| | - Wen-Jie Zhang
- Department of Anesthesiology, Shanghai Gongli Hospital, the Second Military Medical University, Shanghai, P. R. China
| | - Zhen-Zhou Li
- Ningxia Medical University, Gongli Hospital of Shanghai Pudong New Area Training Base, Shanghai, P. R. China
| | - Jian-Rong Guo
- Department of Anesthesiology, Shanghai Gongli Hospital, the Second Military Medical University, Shanghai, P. R. China.,Ningxia Medical University, Gongli Hospital of Shanghai Pudong New Area Training Base, Shanghai, P. R. China
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Abstract
Objectives: Expound upon priorities for basic/translational science identified in a recent paper by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data Sources: Original paper, search of the literature. Study Selection: By several members of the original task force with specific expertise in basic/translational science. Data Extraction: None. Data Synthesis: None. Conclusions: In the first of a series of follow-up reports to the original paper, several members of the original task force with specific expertise provided a more in-depth analysis of the five identified priorities directly related to basic/translational science. This analysis expounds on what is known about the question and what was identified as priorities for ongoing research. It is hoped that this analysis will aid the development of future research initiatives.
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Sun JK, Zhou J, Sun XP, Shen X, Zhu DM, Wang X, Zhou SM, Mu XW. Interleukin-9 promotes intestinal barrier injury of sepsis: a translational research. J Intensive Care 2021; 9:37. [PMID: 33941281 PMCID: PMC8091144 DOI: 10.1186/s40560-021-00550-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 04/25/2021] [Indexed: 12/29/2022] Open
Abstract
Background Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Intestinal mucosal barrier injury is one of the important manifestations of sepsis. Interleukin-9 (IL-9) and IL-9-producing CD4(+) T cells were emerging pro-inflammatory mediators with development of intestinal injury. However, it is unclear whether IL-9 is related to the intestinal barrier injury of sepsis. Methods To investigate the roles of IL-9-producing CD4(+) T cells and IL-9 in the process of barrier injury in sepsis, serum IL-9-producing CD4(+) T cell percentages, IL-9, and D-lactate levels were measured in septic patients and controls. The markers of barrier function in serum and intestinal tissue were also collected in septic rats. Moreover, the barrier injury degree and survival rate of septic rats were also investigated after increasing or interfering with IL-9 expression. Results The serum IL-9-producing CD4(+) T cell percentages, IL-9, and D-lactate levels were significantly higher in septic patients or rats than those in controls. IL-9-producing CD4(+) T cells and IL-9 levels were positively correlated with D-lactate levels and had a high predictive value of 28-day mortality in septic patients. The non-survivors had significantly higher serum T cell percentages, IL-9, and D-lactate levels compared with survivors. In septic rats, IL-9 increased the expression levels of D-lactate, whereas that decreased the expression levels of zonula occludens 1. Moreover, the barrier injury was aggravated or alleviated by increasing or interfering with IL-9 expression, respectively. Survival rate analysis also showed that IL-9 decreased the 14-day survival rate of septic rats. Conclusion IL-9 is closely related to intestinal mucosal barrier injury and mortality in sepsis. IL-9 blockade has the potential to improve the barrier injury in sepsis. Trial registration The study was registered at ClinicalTrials.gov (ID: NCT03791866, Date: December 2018).
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Affiliation(s)
- Jia-Kui Sun
- Department of Geriatrics Intensive Care Unit, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province People's Hospital), 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China.,Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, Jiangsu Province, China
| | - Jing Zhou
- Department of Geriatrics Intensive Care Unit, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province People's Hospital), 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Xin-Pei Sun
- Department of General Office, Productivity Center of Jiangsu Province, 175 Longpan Road, Nanjing, 210042, Jiangsu Province, China
| | - Xiao Shen
- Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, Jiangsu Province, China
| | - Dong-Mei Zhu
- Department of Geriatrics Intensive Care Unit, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province People's Hospital), 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Xiang Wang
- Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, Jiangsu Province, China.
| | - Su-Ming Zhou
- Department of Geriatrics Intensive Care Unit, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province People's Hospital), 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China.
| | - Xin-Wei Mu
- Department of Critical Care Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, Jiangsu Province, China.
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Vatsalya V, Li F, Frimodig J, Gala KS, Srivastava S, Kong M, Ramchandani VA, Feng W, Zhang X, McClain CJ. Repurposing Treatment of Wernicke-Korsakoff Syndrome for Th-17 Cell Immune Storm Syndrome and Neurological Symptoms in COVID-19: Thiamine Efficacy and Safety, In-Vitro Evidence and Pharmacokinetic Profile. Front Pharmacol 2021; 11:598128. [PMID: 33737877 PMCID: PMC7960760 DOI: 10.3389/fphar.2020.598128] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 12/10/2020] [Indexed: 12/19/2022] Open
Abstract
Coronavirus disease identified in 2019 (COVID-19) can be complicated by the Th17 cell-mediated IL-17 proinflammatory response. We tested if thiamine can effectively lower the Th17 response in a clinical study [Proinflammatory state in alcohol use disorder patients termed as disease controls (DC)] and corroborated the results using an in vitro study. We developed an effective dose range and model for key pharmacokinetic measures with the potential of targeting the cytokine storm and neurological symptoms of COVID-19. Three-week 200 mg dose of thiamine was administered to sixteen DC patients. Eight healthy volunteers (HV) were also included in this investigation. A subsequent in vitro study was performed to validate the effectiveness of thiamine [100 mg/day equivalent (0.01 μg/ml)] treatment in lowering the Th17 proinflammatory response in a mouse macrophage cell line (RAW264.7) treated with ethanol. Based on recent publications, we compared the results of the IL-17 response from our clinical and in vitro study to those found in other proinflammatory disease conditions (metabolic conditions, septic shock, viral infections and COVID-19) and effective and safe dose ranges of thiamine. We developed a pharmacokinetic profile for thiamine dose range as a novel intervention strategy in COVID-19. DC group showed significantly elevated proinflammatory cytokines compared to HV. Thiamine-treated DC patients showed significant lowering in IL-17 and increase in the IL-22 levels. In humans, a range of 79-474 mg daily of thiamine was estimated to be effective and safe as an intervention for the COVID-19 cytokine storm. A literature review showed that several neurological symptoms of COVID-19 (∼45.5% of the severe cases) occur in other viral infections and neuroinflammatory states that may also respond to thiamine treatment. Thiamine, a very safe drug even at very high doses, could be repurposed for treating the Th17 mediated IL-17 immune storm, and the subsequent neurological symptoms observed in COVID-19. Further studies using thiamine as an intervention/prevention strategy in COVID-19 patients could identify its precise anti-inflammatory role.
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Affiliation(s)
- Vatsalya Vatsalya
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Robley Rex VA Medical Center, Louisville, KY, United States
| | - Fengyuan Li
- Department of Medicine, University of Louisville, Louisville, KY, United States
- University of Louisville Alcohol Research Center, Louisville, KY, United States
| | - Jane Frimodig
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Robley Rex VA Medical Center, Louisville, KY, United States
| | - Khushboo S. Gala
- Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Shweta Srivastava
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Envirome Institute, University of Louisville, Louisville, KY, United States
| | - Maiying Kong
- Robley Rex VA Medical Center, Louisville, KY, United States
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, United States
| | - Vijay A. Ramchandani
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, United States
| | - Wenke Feng
- Department of Medicine, University of Louisville, Louisville, KY, United States
- University of Louisville Alcohol Research Center, Louisville, KY, United States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, United States
- University of Louisville Hepatobiology and Toxicology COBRE, Louisville, KY, United States
| | - Xiang Zhang
- University of Louisville Alcohol Research Center, Louisville, KY, United States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, United States
- University of Louisville Hepatobiology and Toxicology COBRE, Louisville, KY, United States
- Department of Chemistry, University of Louisville, Louisville, KY, United States
- Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY, United States
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Robley Rex VA Medical Center, Louisville, KY, United States
- University of Louisville Alcohol Research Center, Louisville, KY, United States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, United States
- University of Louisville Hepatobiology and Toxicology COBRE, Louisville, KY, United States
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Li H, Liu R, Zhang R, Zhang S, Wei Y, Zhang L, Zhou H, Yang C. Protective Effect of Arbidol Against Pulmonary Fibrosis and Sepsis in Mice. Front Pharmacol 2021; 11:607075. [PMID: 33584285 PMCID: PMC7873045 DOI: 10.3389/fphar.2020.607075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/30/2020] [Indexed: 01/08/2023] Open
Abstract
From the perspective of epidemiology, viral immunology and current clinical research, pulmonary fibrosis may become one of the complications of patients with Coronavirus Disease 2019 (COVID-19). Cytokine storm is a major cause of new coronavirus death. The purpose of this study was to explore the effects of antiviral drug arbidol on cytokine storm and pulmonary fibrosis. Here, we use a mouse model of bleomycin-induced pulmonary fibrosis and a mouse model of fecal dilution-induced sepsis to evaluate the effects of arbidol on pulmonary fibrosis and cytokine storm. The results showed that arbidol significantly reduced the area of pulmonary fibrosis and improved lung function (reduced inspiratory resistance, lung dynamic compliance and forced vital capacity increased). Treatment with arbidol promoted reduced sepsis severity 48 h after sepsis induction, based on weight, murine sepsis score and survival rate. Arbidol observably alleviates inflammatory infiltrates and injury in the lungs and liver. Finally, we also found that arbidol reduced serum levels of pro-inflammatory factors such as TNF-α and IL-6 induced by fecal dilution. In conclusion, our results indicate that arbidol can alleviate the severity of pulmonary fibrosis and sepsis, and provide some reference for the treatment of cytokine storm and sequelae of pulmonary fibrosis in patients with COVID-19.
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Affiliation(s)
- Hailong Li
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,High-Throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Rui Liu
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,High-Throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Ruotong Zhang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,High-Throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Shanshan Zhang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Yiying Wei
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,High-Throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Liang Zhang
- Department of Thoracic Surgery, Tian Jin First Central Hospital, Tianjin, China
| | - Honggang Zhou
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,High-Throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Cheng Yang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.,High-Throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, China
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MicroRNA-155: Regulation of Immune Cells in Sepsis. Mediators Inflamm 2021; 2021:8874854. [PMID: 33505221 PMCID: PMC7810547 DOI: 10.1155/2021/8874854] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 12/15/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs are small noncoding RNAs which regulate gene expression at the posttranscriptional level. miR-155 is encoded by the miR-155 host gene (miR155HG), also known as the noncoding B cell integration cluster (BIC). MicroRNAs are widely expressed in various hematopoietic cells and are involved in regulating the immune system. In this review, we summarized how miR-155 modulates specific immune cells and the regulatory role of miR-155 in sepsis. miR-155 is expressed by different populations of innate and adaptive immune cells and is involved in the regulation of development, proliferation, and function in these cells. Sepsis is associated with uncontrollable inflammatory responses, accompanied by unacceptably high mortality. Due to the inadequacy of diagnostic markers as well as treatment strategies, treating sepsis can be a huge challenge. So far, a large number of experiments have shown that the expression of miR-155 is increased at an early stage of sepsis and that this increase is positively correlated with disease progression and severity. In addition, by blocking the proinflammatory effects of miR-155, it can effectively improve sepsis-related organ injury, providing novel insights to identify potential biomarkers and therapeutic targets for sepsis. However, since most of the current research is limited to animal experiments, further clinical research is required to determine the function of miR-155 and its mechanism related to sepsis.
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Zhang S, Wu Z, Chang W, Liu F, Xie J, Yang Y, Qiu H. Classification of Patients With Sepsis According to Immune Cell Characteristics: A Bioinformatic Analysis of Two Cohort Studies. Front Med (Lausanne) 2020; 7:598652. [PMID: 33344482 PMCID: PMC7744969 DOI: 10.3389/fmed.2020.598652] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/30/2020] [Indexed: 12/29/2022] Open
Abstract
Background: Sepsis is well-known to alter innate and adaptive immune responses for sustained periods after initiation by an invading pathogen. Identification of immune cell characteristics may shed light on the immune signature of patients with sepsis and further indicate the appropriate immune-modulatory therapy for distinct populations. Therefore, we aimed to establish an immune model to classify sepsis into different immune endotypes via transcriptomics data analysis of previously published cohort studies. Methods: Datasets from two observational cohort studies that included 585 consecutive sepsis patients admitted to two intensive care units were downloaded as a training cohort and an external validation cohort. We analyzed genome-wide gene expression profiles in blood from these patients by using machine learning and bioinformatics. Results: The training cohort and the validation cohort had 479 and 106 patients, respectively. Principal component analysis indicated that two immune subphenotypes associated with sepsis, designated the immunoparalysis endotype, and immunocompetent endotype, could be distinguished clearly. In the training cohort, a higher cumulative 28-day mortality was found in patients classified as having the immunoparalysis endotype, and the hazard ratio was 2.32 (95% CI: 1.53–3.46 vs. the immunocompetent endotype). External validation further demonstrated that the present model could categorize sepsis into the immunoparalysis and immunocompetent type precisely and efficiently. The percentages of 4 types of immune cells (M0 macrophages, M2 macrophages, naïve B cells, and naïve CD4 T cells) were significantly associated with 28-day cumulative mortality (P < 0.05). Conclusion: The present study developed a comprehensive tool to identify the immunoparalysis endotype and immunocompetent status in hospitalized patients with sepsis and provides novel clues for further targeting of therapeutic approaches.
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Affiliation(s)
- Shi Zhang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zongsheng Wu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Wei Chang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Feng Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jianfeng Xie
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yi Yang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Haibo Qiu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
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Therapeutic Prospects for Th-17 Cell Immune Storm Syndrome and Neurological Symptoms in COVID-19: Thiamine Efficacy and Safety, In-vitro Evidence and Pharmacokinetic Profile. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2020. [PMID: 32869036 DOI: 10.1101/2020.08.23.20177501] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Introduction Emerging infectious diseases, especially the coronavirus disease identified in 2019 (COVID-19), can be complicated by a severe exacerbation in the Th17 cell-mediated IL-17 proinflammatory immune storm. This enhanced immune response plays a major role in mortality and morbidity, including neurological symptoms. We hypothesized that countering the cytokine storm with thiamine may have therapeutic efficacy in lowering the Th17 cell proinflammatory response. We used an in vitro study and corroborated those results in disease controls (DC). We developed an effective dose range and model for key pharmacokinetic measures with the potential of targeting the cytokine storm and neurological symptoms of COVID-19. Study Participants and Methods We investigated the effect of a three-week 200 mg dose of thiamine in lowering the Th17 response in sixteen DC (proinflammatory origin due to heavy alcohol drinking) patients; and eight healthy control/volunteers (HV) as a pilot clinical-translational investigation. To further investigate, we performed an in vitro study evaluating the effectiveness of thiamine treatment in lowering the Th17 proinflammatory response in a mouse macrophage cell line (RAW264.7) treated with ethanol. In this in vitro study, 100 mg/day equivalent (0.01 ug/ml) thiamine was used. Based on recent publications, we compared the results of the IL-17 response from our clinical and in vitro study to those found in other proinflammatory disease conditions (metabolic conditions, septic shock, viral infections and COVID-19), including symptoms, and dose ranges of effective and safe administration of thiamine. We developed a dose range and pharmacokinetic profile for thiamine as a novel intervention strategy in COVID-19 to alleviate the effects of the cytokine storm and neurological symptoms. Results The DC group showed significantly elevated proinflammatory cytokines compared to HV. Three-week of 200 mg daily thiamine treatment significantly lowered the baseline IL-17 levels while increased IL-22 levels (anti-inflammatory response). This was validated by an in vitro macrophage response using a lower thiamine dose equivalent (100 mg), which resulted in attenuation of IL-17 and elevation of IL-22 at the mRNA level compared to the ethanol-only treated group. In humans, a range of 79-474 mg daily of thiamine was estimated to be effective and safe as an intervention for the COVID-19 cytokine storm. A literature review showed that several neurological symptoms of COVID-19 (which exist in 45.5% of the severe cases) occur in other viral infections and neuroinflammatory states that may also respond to thiamine treatment. Discussion The Th17 mediated IL-17 proinflammatory response can potentially be attenuated by thiamine. Thiamine, a very safe drug even at very high doses, could be repurposed for treating the cytokine/immune storm of COVID-19 and the subsequent neurological symptoms observed in COVID-19 patients. Further studies using thiamine as an interventional/prevention strategy in severe COVID-19 patients could identify its precise anti-inflammatory role.
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Li G, Zhang L, Han N, Zhang K, Li H. Increased Th17 and Th22 Cell Percentages Predict Acute Lung Injury in Patients with Sepsis. Lung 2020; 198:687-693. [PMID: 32462370 DOI: 10.1007/s00408-020-00362-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 05/08/2020] [Indexed: 12/15/2022]
Abstract
PURPOSE This study was conducted to investigate the percentages of Th22 and Th17 cells in the peripheral blood of septic patients with and without acute lung injury (ALI) and their clinical significance. METHODS A total of 479 patients were divided into non-ALI and ALI groups. The percentages of Th22 and Th17 cells and the levels of interleukin 22 (IL-22), 6 (IL-6), and 17 (IL-17) were determined. Receiver operating characteristic curve analysis was performed to assess the diagnostic value of Th22 and Th17 cells to predict sepsis-induced ALI. RESULTS The lung injury prediction score (LIPS), IL-6, IL-17, and IL-22 levels and the percentages of Th17 and Th22 cells were significantly higher in the ALI group (P < 0.05). They were significant factors affecting sepsis-induced ALI (P < 0.05). Multivariate logistic regression analysis showed that the LIPS (OR = 1.130), IL-17 (OR = 1.982), IL-22 (OR = 2.612) and the percentages of Th17 (OR = 2.211) and Th22 (OR = 3.230) cells were independent risk factors for ALI. The area under the curve of Th22 cells was 0.844 to predict ALI with a cutoff value of 6.81%. The sensitivity and specificity for early diagnosis of sepsis-induced ALI by the Th22 cell percentage were 78.72% and 89.13%, respectively. CONCLUSIONS Th22 and Th17 cells in peripheral blood are significantly increased in septic patients with ALI and they may be used as biomarkers for early diagnosis of sepsis-induced ALI.
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Affiliation(s)
- Gang Li
- Department of Emergency Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, China.
| | - Liangtian Zhang
- Department of Critical Care Medicine, Chunan First People's Hospital, Zhejiang Provincial People's Hospital Chunan Branch, Chunan, China
| | - Nannan Han
- Department of Emergency Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, China
| | - Ke Zhang
- Department of Emergency Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, China
| | - Hengjie Li
- Department of Emergency Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, 158 Shangtang Road, Hangzhou, 310014, China
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Xia H, Wang F, Wang M, Wang J, Sun S, Chen M, Huang S, Chen X, Yao S. Maresin1 ameliorates acute lung injury induced by sepsis through regulating Th17/Treg balance. Life Sci 2020; 254:117773. [PMID: 32418896 DOI: 10.1016/j.lfs.2020.117773] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 05/07/2020] [Accepted: 05/07/2020] [Indexed: 12/17/2022]
Abstract
The disturbance of the immune homeostasis caused by infection is decisive for multiple organ dysfunction caused by sepsis. Both the th17 cell and the regulatory cell(Tregs) are important components of the immune system and play a crucial role in maintaining immune homeostasis. In this study, we explored the effect of Maresin1, an emerging specific pro-inflammatory mediator, on the balance of Th17/Treg in sepsis, and investigated the underlying mechanism. We used the male C57BL/6 mice to establish the model of sepsis-induced lung injury by cecal ligation and puncture to verify the protective effect of Maresin1. Our study showed that Maresin1 could significantly inhibit the excessive inflammatory response and promote the inflammation regression in the process of sepsis-induced acute lung injury, thereby reducing lung damage and improving lung function. These effects were accompanied with the regulation of Maresin1 on the Th17/Treg balance in the early stages of sepsis. We demonstrated that Maresin1 has a certain effect on increasing the number of Treg and decreasing the number of Th17 cells in the early stages of sepsis, which is consistent with its effect on STAT3/RORγt and STAT5/Foxp3 signal pathways. Our study elucidated for the first time the relationship between Maresin1 and Th17/Treg balance in sepsis-induced acute lung injury.
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Affiliation(s)
- Haifa Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Fuquan Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Min Wang
- Department of Emergency and Intensive Care Unit, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Jingxu Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shujun Sun
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ming Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shiqian Huang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiangdong Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Shanglong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Deutschman CS, Hellman J, Roca RF, De Backer D, Coopersmith CM. The surviving sepsis campaign: basic/translational science research priorities. Intensive Care Med Exp 2020; 8:31. [PMID: 32676795 PMCID: PMC7365694 DOI: 10.1186/s40635-020-00312-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Objectives Expound upon priorities for basic/translational science identified in a recent paper by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data sources Original paper, search of the literature. Study selection This study is selected by several members of the original task force with specific expertise in basic/translational science. Data extraction and data synthesis are not available. Conclusions In the first of a series of follow-up reports to the original paper, several members of the original task force with specific expertise provided a more in-depth analysis of the five identified priorities directly related to basic/translational science. This analysis expounds on what is known about the question and what was identified as priorities for ongoing research. It is hoped that this analysis will aid the development of future research initiatives.
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Affiliation(s)
- Clifford S Deutschman
- Department of Pediatrics, Hofstra/Northwell School of Medicine and the Feinstein Institute for Medical Research/Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, USA. .,Department of Molecular Medicine, Hofstra/Northwell School of Medicine and the Feinstein Institute for Medical Research/Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, USA.
| | - Judith Hellman
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA
| | - Ricard Ferrer Roca
- Intensive Care Department, Vall d'Hebron University Hospital, Barcelona, Spain.,Shock, Organ Dysfunction and Resuscitation (SODIR) Research Group, Vall d'Hebron Institut de Recerca, Barcelona, Spain
| | - Daniel De Backer
- Chirec Hospitals, Université Libre de Bruxelles, Brussels, Belgium
| | - Craig M Coopersmith
- Department of Surgery and Emory Critical Care Center, Emory University, Atlanta, GA, USA
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Baicalin suppresses Th1 and Th17 responses and promotes Treg response to ameliorate sepsis-associated pancreatic injury via the RhoA-ROCK pathway. Int Immunopharmacol 2020; 86:106685. [PMID: 32570032 DOI: 10.1016/j.intimp.2020.106685] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/24/2020] [Accepted: 06/04/2020] [Indexed: 12/23/2022]
Abstract
Recent studies have reported that the imbalance of T helper 1 cell (Th1), Th17 and regulatory T cell (Treg) have been confirmed to play a vital role in the development of sepsis and other inflammatory diseases. Baicalin (BA) has anti-inflammatory properties and improves survival in sepsis. We investigated whether baicalin could regulate Th1, Th17 and Treg responses to ameliorate sepsis-associated pancreatic injury through the ras homolog family member A (RhoA)-Rho kinase (ROCK) pathway. The sepsis model was established by using the cecal ligation and puncture (CLP) method. Fifty mice were randomly divided into five groups (n = 10): sham group, model group, low-dose group (BA-L, 100 mg/kg of baicalin), medium-dose group (BA-M, 200 mg/kg of baicalin) and highdose group (BA-H, 300 mg/kg of baicalin). The effects of baicalin on the pancreatic injury, on changes of Th1, Th17 and Treg cells in vivo and in vitro, on RhoA, ROCK1 and signal transducer and activator of transcription (STAT) signaling pathways, and on levels of interferon-γ (IFN-γ), interleukin-17 (IL-17) and IL-10 were examined. Treatment of the CLP mice with baicalin significantly reduced the extent, scope and severity of the pathological changes of sepsis-associated pancreatic injury. Baicalin evidently reduced Th1 and Th17 cells and increased Treg cells in peripheral blood, spleen, pancreatic tissue and significantly inhibited T-box protein expressed in T cells (T-bet), retinoic acid receptor-related orphan receptor γt (RORγt) and increased forkhead/winged helix transcription factor (Foxp3) expressions in the pancreatic tissue. Baicalin reduced the expressions of RhoA, ROCK1, phosphorylated STAT4 (p-STAT4), p-STAT3 and increased the expression of p-STAT5 in peripheral blood, spleen and pancreatic tissue. Baicalin reduced the expressions of IFN-γ and IL-17 and increased the IL-10 in serum and pancreatic tissue. Baicalin is capable of ameliorating sepsis-associated pancreatic injury and regulating Th1, Th17 and Treg responses in sepsis. The present study provided a potential adjunctive therapy for treating pancreatic injury in sepsis, and further study is needed to reveal its deeper mechanisms.
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Cheng W, Wang H, Zhang J, Bai G, Han W, Chen J, Cui N. Lymphocyte subset counts as diagnostic and prognostic markers for carbapenem-resistant Enterobacteriaceae (CRE) infection in critically ill patients. Int J Infect Dis 2020; 96:315-322. [PMID: 32389844 DOI: 10.1016/j.ijid.2020.04.072] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/07/2020] [Accepted: 04/25/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES This study investigated the use of lymphocyte subset counts as diagnostic and prognostic markers for carbapenem-resistant Enterobacteriaceae (CRE) infection. METHODS We assessed the lymphocyte subset populations and other clinical parameters of septic patients upon intensive care unit (ICU) admission, and evaluated their potential impact on CRE infection diagnosis and outcome. RESULTS Among 373 septic patients, 51 were diagnosed with CRE infection. The 28-day mortality was significantly higher in CRE than non-CRE patients (35.3% vs 14.9%). The T lymphocyte count and CD4+CD28+ T cell count were both independent risk factors for CRE infection, with the latter had the best diagnostic ability (AUC: 0.908; p < 0.0001). Lower CD4+CD28+ T cell counts were associated with higher likelihoods of CRE infection. The CRE incidence and 28-day mortality of CRE-infected patients could be predicted using cutoff values of 242 (sensitivity: 83.9%; specificity: 87.5%) and 58.5 (sensitivity: 100%; specificity: 61.1%) CD4+CD28+ T cells/μl at ICU admission, respectively. CONCLUSIONS Septic patients with CRE infection had higher 28-day mortality. Given that the CD4+CD28+ T cell count was significantly lower in CRE than non-CRE septic patients and a lower cell count was significantly associated with higher 28-day mortality, CD4+CD28+ T cell counts may be useful markers for early diagnosis of CRE infection and outcome prediction.
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Affiliation(s)
- Wei Cheng
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Hao Wang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Jiahui Zhang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Guangxu Bai
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Wen Han
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Jianwei Chen
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Na Cui
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China.
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Bai G, Wang H, Han W, Cui N. T-Bet Expression Mediated by the mTOR Pathway Influences CD4 + T Cell Count in Mice With Lethal Candida Sepsis. Front Microbiol 2020; 11:835. [PMID: 32431684 PMCID: PMC7214724 DOI: 10.3389/fmicb.2020.00835] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 04/07/2020] [Indexed: 11/13/2022] Open
Abstract
The sustained high morbidity and mortality of Candida sepsis are mainly caused by compromise of host immunity. Clinically, it is often manifested as a significant decrease in CD4+ T cell count, although the mechanism is unclear. We established a lethal mice Candida sepsis model and used Murine Sepsis Score to group mice with different disease severity to establish the influence of T-bet expression on CD4+ T cell count in Candida sepsis. We found that CD4+ T cell count decreased in Candida-infected compared to uninfected mice, and the degree of decrease increased with aggravation of sepsis. Expression of T-bet similarly decreased with worsening of sepsis, but it was significantly enhanced in candidiasis in comparison of naïve state. To clarify its possible mechanism, we measured the activity of mammalian target of rapamycin (mTOR), which is a key regulator of T-bet expression. The mTOR pathway was activated after infection and its activity increased with progression of sepsis. We used mice with T-cell-specific knockout of mTOR or tuberous sclerosis complex (TSC)1 to further inhibit or strengthen the mTOR signaling pathway. We found that mTOR deletion mice had a higher CD4+ T cell count by regulating T-bet expression, and the result in TSC1 deletion mice was reversed. These results demonstrate that T-bet expression mediated by the mTOR pathway influences the CD4+ T cell count in mice with Candida sepsis.
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Affiliation(s)
- Guangxu Bai
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Hao Wang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Wen Han
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Na Cui
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China
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Xu J, Li J, Xiao K, Zou S, Yan P, Xie X, Xie L. Dynamic changes in human HLA-DRA gene expression and Th cell subsets in sepsis: Indications of immunosuppression and associated outcomes. Scand J Immunol 2019; 91:e12813. [PMID: 31386235 DOI: 10.1111/sji.12813] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 07/11/2019] [Accepted: 07/31/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Sepsis is a life-threatening disease that is an immune disorder response that causes multiple organ dysfunction. In this study, we investigated the dynamic changes in mRNA expression of HLA-DRA gene and the specific transcription factor of helper T cell subsets to explore long-term immunophenotyping and its relationship with prognosis. METHODS Seventy-eight sepsis patients and twelve healthy controls were recruited in this study. Blood samples were collected at eight-time points during their septic course and were assayed for the gene expression of HLA-DRA and T helper cell subset-specific transcription factors (T-bet: Th1, GATA3: Th2, Foxp3: Treg, RORC: Th17). RESULTS The levels of HLA-DRA in survivors gradually increased but were maintained at lower levels in non-survivors. The specific transcription factor of Th1 and Th2 cells, T-bet and GATA-3 were significantly lower in sepsis patients than in normal controls, and the non-survivors showed significantly lower levels than the survivors (P < .05). RORC and FOXP3, the specific transcription factor of Treg and Th17 were significantly higher in survivors than in non-survivors and normal controls (P < .05). T-bet and GATA-3 had a linear correlation with HLA-DRA expression (P < .01). CONCLUSIONS The dynamic changes in HLA-DRA expression in peripheral blood could accurately reflect the immune status of sepsis patients, and the reduction in HLA-DRA may be an important reason for abnormal T cell differentiation. The sustained low levels of the Th cell subsets (Th1 and Th2) suggest the suppression of adaptive immunity, and this persistent immunosuppression may be the leading cause of death in septic patients.
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Affiliation(s)
- Jianqiao Xu
- Department of Pulmonary and Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China
| | - Jia Li
- Department of Respiratory and Critical Care Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Kun Xiao
- Department of Pulmonary and Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China
| | - Sifan Zou
- Department of Pulmonary and Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Peng Yan
- Department of Pulmonary and Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China
| | - Xiaowei Xie
- Department of Respiratory and Critical Care Medicine, the first affiliated hospital of the Chinese PLA General Hospital, Beijing, China
| | - Lixin Xie
- Department of Pulmonary and Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China
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Sun JK, Zhang WH, Chen WX, Wang X, Mu XW. Effects of early enteral nutrition on Th17/Treg cells and IL-23/IL-17 in septic patients. World J Gastroenterol 2019; 25:2799-2808. [PMID: 31236002 PMCID: PMC6580355 DOI: 10.3748/wjg.v25.i22.2799] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/04/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The imbalance of Th17/Treg cells and the IL-23/IL-17 axis have been confirmed to be associated with sepsis and various inflammatory diseases. Early enteral nutrition (EEN) can modulate the inflammatory response, improve immune dysfunction, and prevent enterogenic infection in critically ill patients; however, the precise mechanisms remain unclear. Considering the important roles of Th17 and Treg lymphocytes in the development of inflammatory and infectious diseases, we hypothesized that EEN could improve the immune dysfunction in sepsis by maintaining a balanced Th17/Treg cell ratio and by regulating the IL-23/IL-17 axis.
AIM To investigate the effects of EEN on the Th17/Treg cell ratios and the IL-23/IL-17 axis in septic patients.
METHODS In this prospective clinical trial, patients were randomly divided into an EEN or delayed enteral nutrition (DEN) group. Enteral feeding was started within 48 h in the EEN group, whereas enteral feeding was started on the 4th day in the DEN group. The Th17 and Treg cell percentages and the interleukin levels were tested on days 1, 3, and 7 after admission. The clinical severity and outcome variables were also recorded.
RESULTS Fifty-three patients were enrolled in this trial from October 2017 to June 2018. The Th17 cell percentages, Th17/Treg cell ratios, IL-17, IL-23, and IL-6 levels of the EEN group were lower than those of the DEN group on the 7th day after admission (P < 0.05). The duration of mechanical ventilation and of the intensive care unit stay of the EEN group were shorter than those of the DEN group (P < 0.05). However, no difference in the 28-d mortality was found between the two groups (P = 0.728).
CONCLUSION EEN could regulate the imbalance of Th17/Treg cell ratios and suppress the IL-23/IL-17 axis during sepsis. Moreover, EEN could reduce the clinical severity of sepsis but did not reduce the 28-d mortality of septic patients.
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Affiliation(s)
- Jia-Kui Sun
- Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu Province, China
| | - Wen-Hao Zhang
- Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu Province, China
| | - Wen-Xiu Chen
- Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu Province, China
| | - Xiang Wang
- Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu Province, China
| | - Xin-Wei Mu
- Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu Province, China
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Xue M, Xie J, Liu L, Huang Y, Guo F, Xu J, Yang Y, Qiu H. Early and dynamic alterations of Th2/Th1 in previously immunocompetent patients with community-acquired severe sepsis: a prospective observational study. J Transl Med 2019; 17:57. [PMID: 30813927 PMCID: PMC6391803 DOI: 10.1186/s12967-019-1811-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 02/21/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND T helper (Th) cells regulate sepsis processes, including primary pathogen clear and secondary pathogen defence. The objectives of this study were to determine the early and dynamic alterations of Th1 and Th2 populations to community-acquired severe sepsis upon onset among previously immunocompetent patients and whether it was related to clinical outcomes. METHODS This prospective observational cohort study was conducted at a general intensive care unit (ICU) of a tertiary teaching hospital in China. Immunocompetent patients with community-acquired severe sepsis within 24 h upon onset were included as septic group. Healthy volunteers and critically ill patients without severe sepsis were recruited as controls. Whole blood was collected on D0, 3rd day (D3) and 7th day (D7) for septic group and once upon enrollment for controls. Th1 and Th2 populations were measured by flow cytometry and assessed for associations with 28-day mortality using cox proportional hazard models. Associations of dynamic alterations of Th cell subpopulations with clinical outcomes were investigated. RESULTS This study demonstrated that community-acquired severe sepsis patients (n = 71) had increased Th2/Th1 and Th2 populations, compared to healthy controls (n = 7) and critically ill patients without severe sepsis (n = 7) at admission. Among the septic cohort, values of Th2/Th1 were significantly higher in non-survivors than survivors on D0 (p = 0.04), D3 (p < 0.001) and D7 (p < 0.001). Patients with persistently increasing Th2/Th1 demonstrated the highest mortality (47.1%) and incidence of ICU-acquired infections (64.7%). CONCLUSIONS Th2/Th1 was markedly up-regulated with Th2 dominance upon community-acquired severe sepsis onset among previously immunocompetent patients and its persistently dynamic increase was associated with ICU-acquired infections and 28-day death. Trial registration Institutional Ethics Committee of Zhongda Hospital, 2014ZDSYLL086, registered in June 2014-prospectively registered; ClinicalTrials.gov, NCT02883218, registered on 25 Aug 2016-retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT02883218?cond=NCT02883218&rank=1.
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Affiliation(s)
- Ming Xue
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Jianfeng Xie
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Ling Liu
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Yingzi Huang
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Fengmei Guo
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Jingyuan Xu
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Yi Yang
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Haibo Qiu
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China.
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Hu ZQ, Yao YM, Chen W, Bian JL, Zhao LJ, Chen LW, Hong GL, Lu ZQ, Zhao GJ. Partial Depletion of Regulatory T Cells Enhances Host Inflammatory Response Against Acute Pseudomonas aeruginosa Infection After Sepsis. Inflammation 2019; 41:1780-1790. [PMID: 29956070 DOI: 10.1007/s10753-018-0821-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Immune dysfunction contributes to secondary infection and worse outcomes in sepsis. Regulatory T cells (Tregs) have been implicated in sepsis-induced immunosuppression. Nevertheless, the role of Tregs in secondary infection after sepsis remains to be determined. In the present study, a two-hit model which mimics clinical conditions was used and the potential role of Tregs in secondary Pseudomonas aeruginosa infection post-sepsis was investigated. Results showed that mice were susceptible to secondary P. aeruginosa infection 3 days, but not 7 days, post-cecal ligation and puncture (CLP). The levels of IL-17A, IL-1β, and IL-6 remained low in CLP mice after P. aeruginosa infection, while the levels of IL-10 increased significantly. Additionally, increased number of Tregs in both lung and spleen was observed in "two-hit" mice. Injection with PC61 (anti-CD25) mAb reduced the number of Tregs by 50% in spleen and 60% in lung of septic mice. This partial depletion of Tregs elevated IL-17A, IL-1β, and IL-6 production and decreased IL-10 levels in septic mice with P. aeruginosa infection, leading to lower bacterial load, attenuation of lung injury, and improvement of survival. The present findings demonstrate that Tregs play a crucial role in secondary P. aeruginosa infection after sepsis by modulating the inflammatory response.
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Affiliation(s)
- Zhi-Qiang Hu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Intensive Care Unit, Ningbo First Hospital, Ningbo, 315000, China
| | - Yong-Ming Yao
- Burns Institute, First Affiliated Hospital of PLA General Hospital, Beijing, 100048, China
| | - Wei Chen
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Jia-Lan Bian
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Lin-Jun Zhao
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Long-Wang Chen
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Guang-Liang Hong
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhong-Qiu Lu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. .,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. .,College of Nursing, Wenzhou Medical University, Wenzhou, 325000, China.
| | - Guang-Ju Zhao
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. .,Wenzhou Key Laboratory of Emergency, Critical Care, and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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Fay KT, Chihade DB, Chen CW, Klingensmith NJ, Lyons JD, Ramonell K, Liang Z, Coopersmith CM, Ford ML. Increased mortality in CD43-deficient mice during sepsis. PLoS One 2018; 13:e0202656. [PMID: 30226896 PMCID: PMC6143188 DOI: 10.1371/journal.pone.0202656] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 08/07/2018] [Indexed: 11/18/2022] Open
Abstract
CD43 is a large transmembrane protein involved in T cell activation. Previous studies of CD43-/- mice in viral models have demonstrated a role for CD43 in Th1/Th2 skewing, activation of Foxp3+ Treg, and T cell apoptosis. However, the role of CD43 during sepsis has never been tested. Thus, we interrogated the role of CD43 during sepsis using a murine cecal ligation and puncture (CLP) model, and found that CD43-/- mice demonstrated significantly worsened mortality compared to B6 mice following CLP. Phenotypic analysis of splenocytes isolated 24 h after septic insult revealed significantly increased apoptosis of central memory cells in both CD4+ and CD8+ T cell compartments in CD43-/- septic mice compared to WT septic mice. Furthermore, CD43-/-septic mice exhibited a prominent Th2 skewing following sepsis relative to WT septic mice, as evidenced by a significant decrease in the frequency of IL-2+ CXCR3+ TH1 cells as a significant increase in the frequency of IL-4+ CCR4+ TH2 cells. Finally, septic CD43-/- animals contained significantly fewer CD25+ Foxp3+ TReg cells as compared to WT septic animals. Importantly, depleting CD25+ Treg eliminated the increased mortality observed in CD43-/- mice. Taken together, these data demonstrate an important role of CD43 in modulating immune dysregulation and mortality following sepsis.
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Affiliation(s)
- Katherine T. Fay
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States of America
| | - Deena B. Chihade
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States of America
| | - Ching-Wen Chen
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States of America
| | - Nathan J. Klingensmith
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States of America
| | - John D. Lyons
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States of America
| | - Kimberly Ramonell
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States of America
| | - Zhe Liang
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States of America
| | - Craig M. Coopersmith
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States of America
- Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, United States of America
| | - Mandy L. Ford
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States of America
- Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, United States of America
- * E-mail:
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Qi ZJ, Zhang Q, Liu B, Shao H, Li CS. Early Changes in Circulatory T Helper Type 1, 2, and 17 Cells of Patients with Out-of-Hospital Cardiac Arrest after Successful Cardiopulmonary Resuscitation. Chin Med J (Engl) 2018; 131:2071-2079. [PMID: 30127217 PMCID: PMC6111693 DOI: 10.4103/0366-6999.239300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background Immune disorder is an important feature of patients with out-of-hospital cardiac arrest (OHCA) after the return of spontaneous circulation (ROSC). We investigated the expression of circulatory T helper type (Th) 1, Th2, and Th17 cells to explore the early immune alteration in OHCA patients after ROSC. Methods During July-September 2016 and March-September 2017, 65 consecutive OHCA patients with ROSC >12 h and 30 healthy individuals were enrolled in this study. Clinical and 28-day survival data were collected. Peripheral blood samples were analyzed to evaluate the expression of Th1/Th2/Th17 cells by flow cytometry from OHCA patients after ROSC on days 1 and 3 and from healthy individuals. Results Compared with healthy individuals, T lymphocyte counts and Th1 cell counts decreased on days 1 and 3 after ROSC (1464 [1198, 2152] vs. 779 [481, 1140] vs. 581 [324, 1118]/μl, χ2 = 30.342, P < 0.001; 154 [90, 246] vs. 39 [19, 78] vs. 24 [12, 53]/μl, χ2 = 42.880, P < 0.001), and Th2 and Th17 cell counts decreased on day 3 (17.0 [10.8, 24.0] vs. 9.0 [3.0, 15.5]/μl, Z = -3.228, P = 0.001; 4.7 [2.7, 9.1] vs. 2.7 [1.0, 6.5]/μl, Z = -2.294, P = 0.022). No change in CD4+/CD3+ lymphocyte ratio was seen on day 1 or day 3 (57.9 [49.4, 63.0] vs. 55.4 [46.5, 66.5] vs. 55.4 [50.2, 67.0]%, χ2 = 0.171, P = 0.918). Th1/CD4+ lymphocyte ratio decreased on days 1 and 3 (19.0 [14.0, 24.9] vs. 9.3 [4.6, 13.9] vs. 9.5 [4.9, 13.6]%, χ2 = 25.754, P < 0.001), and Th2/CD4+ lymphocyte ratio increased on day 1 and decreased on day 3 (1.9 [1.2, 2.5] vs. 2.5 [1.6, 4.0] vs. 1.9 [1.6, 3.8]%, χ2 = 6.913, P = 0.032). Th1/Th2 cell ratio also decreased on both days (9.4 [7.3, 13.5] vs. 3.1 [1.9, 5.6] vs. 4.2 [2.8, 5.9], χ2 = 44.262, P < 0.001). Despite an upward trend in the median of Th17/CD4+ lymphocyte ratio in OHCA patients, there was no significant difference compared with healthy individuals (0.9 [0.4, 1.2] vs. 0.7 [0.4, 1.2] vs. 0.6 [0.3, 1.0]%, χ2 = 2.620, P = 0.270). The dynamic expression of Th1/Th2/Th17 cells on days 1 and 3 were simultaneously analyzed in 28/53 OHCA patients who survived >3 days; patients were divided into survivors (n = 10) and nonsurvivors (n = 18) based on 28-day survival. No significant differences in Th1/Th2/Th17 cell counts, ratios in CD4+ lymphocytes, and Th1/Th2 cell ratio were seen between survivors and nonsurvivors on both days (all P > 0.05). There was no difference over time in both survivors and nonsurvivors (all P > 0.05). Conclusion Downregulated T lymphocyte counts, including Th1/Th2/Th17 subsets and Th1/Th2 cell ratio imbalance, occur in the early period after ROSC, that may be involved in immune dysfunction in OHCA patients.
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Affiliation(s)
- Zhi-Jiang Qi
- Department of Emergency, Beijing Chao-Yang Hospital; Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Qiang Zhang
- Department of Emergency, Beijing Chao-Yang Hospital; Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Bo Liu
- Department of Emergency, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Huan Shao
- Department of Emergency, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Chun-Sheng Li
- Department of Emergency, Beijing Chao-Yang Hospital; Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
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Hibbert JE, Currie A, Strunk T. Sepsis-Induced Immunosuppression in Neonates. Front Pediatr 2018; 6:357. [PMID: 30555806 PMCID: PMC6281766 DOI: 10.3389/fped.2018.00357] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 11/02/2018] [Indexed: 12/13/2022] Open
Abstract
Neonates, especially those born preterm, are at increased risk of sepsis and adverse long-term effects associated with infection-related inflammation. Distinct neonatal immune responses and dysregulated inflammation are central to this unique susceptibility. The traditional separation of sepsis into an initial hyper-inflammatory response followed by hypo-inflammation is continually under review with new developments in this area of research. There is evidence to support the association of mortality in the early acute phase of sepsis with an overwhelming hyper-inflammatory immune response. Emerging evidence from adults suggests that hypo- and hyper-inflammation can occur during any phase of sepsis and that sepsis-immunosuppression is associated with increased mortality, morbidity, and risk to subsequent infection. In adults, sepsis-induced immunosuppression (SII) is characterised by alterations of innate and adaptive immune responses, including, but not limited to, a prominent bias toward anti-inflammatory cytokine secretion, diminished antigen presentation to T cells, and reduced activation and proliferation of T cells. It is unclear if sepsis-immunosuppression also plays a role in the adverse outcomes associated with neonatal sepsis. This review will focus on exploring if key characteristics associated with SII in adults are observed in neonates with sepsis.
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Affiliation(s)
- Julie E Hibbert
- Centre for Neonatal Research and Education, University of Western Australia, Perth, WA, Australia
| | - Andrew Currie
- Centre for Neonatal Research and Education, University of Western Australia, Perth, WA, Australia.,School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia
| | - Tobias Strunk
- Centre for Neonatal Research and Education, University of Western Australia, Perth, WA, Australia.,Neonatal Directorate, King Edward Memorial Hospital for Women, Subiaco, WA, Australia
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Ren C, Zhang H, Wu TT, Yao YM. Autophagy: A Potential Therapeutic Target for Reversing Sepsis-Induced Immunosuppression. Front Immunol 2017; 8:1832. [PMID: 29326712 PMCID: PMC5741675 DOI: 10.3389/fimmu.2017.01832] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Accepted: 12/04/2017] [Indexed: 01/17/2023] Open
Abstract
Sepsis remains the leading cause of mortality in intensive care units and an intractable condition due to uncontrolled inflammation together with immune suppression. Dysfunction of immune cells is considered as a major cause for poor outcome of septic patients but with little specific treatments. Currently, autophagy that is recognized as an important self-protective mechanism for cellular survival exhibits great potential for maintaining immune homeostasis and alleviating multiple organ failure, which further improves survival of septic animals. The protective effect of autophagy on immune cells covers both innate and adaptive immune responses and refers to various cellular receptors and intracellular signaling. Multiple drugs and measures are reportedly beneficial for septic challenge by inducing autophagy process. Therefore, autophagy might be an effective target for reversing immunosuppression compromised by sepsis.
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Affiliation(s)
- Chao Ren
- Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Hui Zhang
- Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China
| | - Tian-Tian Wu
- Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China
| | - Yong-Ming Yao
- Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China.,State Key Laboratory of Kidney Disease, The Chinese PLA General Hospital, Beijing, China
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Kuuliala K, Penttilä AK, Kaukonen KM, Mustonen H, Kuuliala A, Oiva J, Hämäläinen M, Moilanen E, Pettilä V, Puolakkainen P, Kylänpää L, Repo H. Signalling Profiles of Blood Leucocytes in Sepsis and in Acute Pancreatitis in Relation to Disease Severity. Scand J Immunol 2017; 87:88-98. [DOI: 10.1111/sji.12630] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 11/03/2017] [Indexed: 12/14/2022]
Affiliation(s)
- K. Kuuliala
- Department of Bacteriology and Immunology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - A. K. Penttilä
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - K.-M. Kaukonen
- Department of Anesthesiology, Intensive Care and Pain Medicine; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - H. Mustonen
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - A. Kuuliala
- Department of Bacteriology and Immunology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - J. Oiva
- Department of Surgery; Kuopio University Hospital; Kuopio Finland
| | - M. Hämäläinen
- The Immunopharmacology Research Group; Faculty of Medicine and Life Sciences; University of Tampere and Tampere University Hospital; Tampere Finland
| | - E. Moilanen
- The Immunopharmacology Research Group; Faculty of Medicine and Life Sciences; University of Tampere and Tampere University Hospital; Tampere Finland
| | - V. Pettilä
- Department of Anesthesiology, Intensive Care and Pain Medicine; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - P. Puolakkainen
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - L. Kylänpää
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - H. Repo
- Department of Bacteriology and Immunology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
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Abstract
Sepsis is caused by a dysregulated host response to infection. Immune responses determine the characteristics of sepsis. The body's protection against infection involves danger signal surveillance and recognition from nonself, effector functions in response to sensing danger signals, homeostatic regulation, and generation of immunologic memory. During sepsis, the immune system is activated by pathogen-associated and host-derived molecular patterns. Detecting these molecular patterns generates multisystem responses. Impaired organ function remote to the site of infection is the unifying feature. The processes by which an appropriate response to a microbial invader change from adaptive to maladaptive and dysregulated remain unclear.
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Sun JK, Yuan ST, Mu XW, Zhang WH, Liu Y, Zou L, Wang X, Zheng SY. Effects of early enteral nutrition on T helper lymphocytes of surgical septic patients: A retrospective observational study. Medicine (Baltimore) 2017; 96:e7702. [PMID: 28796054 PMCID: PMC5556220 DOI: 10.1097/md.0000000000007702] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The aim of this study was to investigate the effects of early enteral nutrition (EEN) on T helper lymphocytes and the subpopulations ratios of surgical septic patients.We performed a retrospective study including 107 eligible patients from February 2014 to December 2015. Patients were divided into EEN, delayed enteral nutrition (DEN), or total parenteral nutrition (TPN) group according to the duration before enteral feeding. Th1, Th2, Th17, and Treg lymphocyte percentages were collected on days 3, 7, and 14 after admission. The disease severity and clinical outcome variables were also recorded.The Th1, Th17 percentages, and Th1/Th2, Th17/Treg ratios of EEN group were significantly lower than those of DEN or TPN group on the 14th day after admission (P < .05). Compared with TPN, DEN might have a tendency to decrease the Th1 and Th17 percentages. EEN could improve the disease severity and clinical outcomes of septic patients, however, no difference on 28-day mortality was found between EEN and DEN group.EEN could improve the dysregulation of Th1/Th2 and Th17/Treg ratios during early stage of sepsis. Compared with DEN, EEN could improve the disease severity and clinical outcomes, but not decrease the 28-day mortality of surgical septic patients.
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Yoon SJ, Kim SJ, Lee SM. Overexpression of HO-1 Contributes to Sepsis-Induced Immunosuppression by Modulating the Th1/Th2 Balance and Regulatory T-Cell Function. J Infect Dis 2017; 215:1608-1618. [DOI: 10.1093/infdis/jix142] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 03/17/2017] [Indexed: 01/07/2023] Open
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