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1
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Kalinski P, Kokolus KM, Gandhi S. Paclitaxel, interferons and functional reprogramming of tumor-associated macrophages in optimized chemo-immunotherapy. J Immunother Cancer 2025; 13:e010960. [PMID: 40389375 PMCID: PMC12090863 DOI: 10.1136/jitc-2024-010960] [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: 11/01/2024] [Accepted: 04/24/2025] [Indexed: 05/21/2025] Open
Abstract
Immune checkpoint inhibition (ICI) targeting programmed cell death protein-1 (PD1) prevents the elimination of activated cytotoxic T lymphocytes (CTLs) by programmed death-ligand 1/2-expressing cancer and myeloid cells in the tumor microenvironment (TME). ICI has shown its effectiveness in many solid tumors, but it lacks activity against "cold" tumors which lack CTL infiltration, including most of the colon, prostate, lung and breast cancers. Metastatic triple-negative breast cancer (TNBC) responds to PD-1 blockade only in 5-20% cases. Chemotherapy has been shown to have a PD1-sensitizing effect in a fraction of patients with TNBC but the underlying mechanism and the reasoning behind its limitation to only a subset of patients are unknown. Recent data demonstrate the key roles played by paclitaxel-driven Toll-like receptor 4 (TLR4) signaling and the resulting activation of type-1 and type-2 interferon pathways in tumor-associated macrophages, resulting in local M2 to M1 transition and enhanced tumor antigen cross-presentation, in the paclitaxel-driven sensitization of "cold" tumors to ICI. These data and the known ability of the TLR4-activated MyD88-NFκB pathway to mobilize both antitumor and tumor-promoting events in the TME provide new tools to enhance the efficacy of chemo-immunotherapy for metastatic, and potentially early, TNBC and other taxane-sensitive cancers.
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Affiliation(s)
- Pawel Kalinski
- Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Kathleen M Kokolus
- Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Shipra Gandhi
- Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
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2
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Liu Z, Su M, Wan P, Zhen X, He L, Liang H. Identification of Natural Killer Cell-Related Genes as Potential Diagnostic Biomarkers for Pediatric Sepsis. APMIS 2025; 133:e70030. [PMID: 40411297 DOI: 10.1111/apm.70030] [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: 01/16/2024] [Revised: 04/16/2025] [Accepted: 05/06/2025] [Indexed: 05/26/2025]
Abstract
Pediatric sepsis is a prevalent severe condition with a high disability rate and mortality. The purpose of this study was to investigate how NK cell-related genes (NKGs) function in the diagnosis of pediatric sepsis. Differential analysis and Venn analysis were utilized to screen differentially expressed NKGs (DE-NKGs) in pediatric sepsis. The PPI network of DE-NKGs was generated using STRING. Candidate drugs are predicted using the CMAP database. miRNA and transcription factor (TF) targeting hub genes were screened using the Networkanalyst website. A total of 22 DE-NKGs were identified, which were mainly enriched in immune-related biological processes. Ten hub genes that were filtered out from DE-NKGs exhibited good diagnostic performance. Immune infiltration analysis revealed that macrophages and neutrophils had higher infiltration abundance in the pediatric sepsis group, whereas NK cells had higher infiltration abundance in the normal group. NKGs (LCK, FCER1G, PRF1, CD247, GZMB, CD2, CCL4, KLRD1, CCL5, and ITGB2) with diagnostic performance were successfully predicted, and some potential miRNAs, TFs, and candidate drugs were also predicted. In conclusion, this study threw light on a comprehensive understanding of the role of NK cells in pediatric sepsis.
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Affiliation(s)
- Zhihong Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning City, China
| | - Minghua Su
- Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning City, China
| | - Peiqi Wan
- Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning City, China
| | - Xiumei Zhen
- Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning City, China
| | - Lixia He
- Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning City, China
| | - Huan Liang
- Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning City, China
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Gao J, Li H, Yue P, Xie D, Li H, Hao K, Li Y, Tian H. Multifunctional endogenous small molecule-derived polymer composite nanoparticles for the treatment of acute sepsis therapy. SCIENCE CHINA MATERIALS 2024; 67:3885-3897. [DOI: 10.1007/s40843-024-3051-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 07/16/2024] [Indexed: 01/04/2025]
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Karayay B, Olze H, Szczepek AJ. Mammalian Inner Ear-Resident Immune Cells-A Scoping Review. Cells 2024; 13:1528. [PMID: 39329712 PMCID: PMC11430779 DOI: 10.3390/cells13181528] [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: 08/18/2024] [Revised: 09/09/2024] [Accepted: 09/10/2024] [Indexed: 09/28/2024] Open
Abstract
BACKGROUND Several studies have demonstrated the presence of resident immune cells in the healthy inner ear. AIM This scoping review aimed to systematize this knowledge by collecting the data on resident immune cells in the inner ear of different species under steady-state conditions. METHODS The databases PubMed, MEDLINE (Ovid), CINAHL (EBSCO), and LIVIVO were used to identify articles. Systematic reviews, experimental studies, and clinical data in English and German were included without time limitations. RESULTS The search yielded 49 eligible articles published between 1979 and 2022. Resident immune cells, including macrophages, lymphocytes, leukocytes, and mast cells, have been observed in various mammalian inner ear structures under steady-state conditions. However, the physiological function of these cells in the healthy cochlea remains unclear, providing an opportunity for basic research in inner ear biology. CONCLUSIONS This review highlights the need for further investigation into the role of these cells, which is crucial for advancing the development of therapeutic methods for treating inner ear disorders, potentially transforming the field of otolaryngology and immunology.
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Affiliation(s)
- Betül Karayay
- Department of Otorhinolaryngology, Head and Neck Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; (B.K.); (H.O.)
| | - Heidi Olze
- Department of Otorhinolaryngology, Head and Neck Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; (B.K.); (H.O.)
| | - Agnieszka J. Szczepek
- Department of Otorhinolaryngology, Head and Neck Surgery, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; (B.K.); (H.O.)
- Faculty of Medicine and Health Sciences, University of Zielona Góra, 65-046 Zielona Góra, Poland
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5
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Selim MA, Suef RA, Saied E, Abdel-Maksoud MA, Almutairi SM, Aufy M, Mousa AA, Mansour MTM, Farag MMS. Peripheral NK cell phenotypic alteration and dysfunctional state post hepatitis B subviral particles stimulation in CHB patients: evading immune surveillance. Front Immunol 2024; 15:1427519. [PMID: 39328404 PMCID: PMC11424423 DOI: 10.3389/fimmu.2024.1427519] [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: 05/03/2024] [Accepted: 08/15/2024] [Indexed: 09/28/2024] Open
Abstract
Background The relationship between chronic hepatitis B (CHB) infection and natural killer (NK) cell dysfunction is well-established, but the specific role of HBV viral antigens in driving NK cell impairment in patients with CHB remains unclear. This study investigates the modulatory effects of hepatitis B virus subviral particles (HBVsvp, a representative model for HBsAg) on the phenotypic regulation (activating and inhibitory receptors), cytokine production and cytotoxic potential of peripheral blood mononuclear cell-derived natural killer cells (PBMCs-derived NK cell), which contributes to NK cell dysfunction in CHB infection, potentially serving as an effective HBV immune evasion strategy by the virus. Methods NK cells were isolated from peripheral blood of patients with CHB (n=5) and healthy individuals (n=5), stimulated with HBVsvp. Subsequent flow cytometric characterization involved assessing changes in activating (NKp46 and NKG2D) and inhibitory (CD94) receptors expression, quantifying TNF-α and IFN- γ cytokine secretion, and evaluating the cytotoxic response against HepG2.2.15 cells with subsequent HBVsvp quantification. Results In CHB patients, in vitro exposure of PBMCs-derived NK cell with HBVsvp (represent HBsAg model) significantly reduced NK cell-activating receptors expression (P = 0.022), increased expression of CD94 + NK cells (p = 0.029), accompanied with a reduced TNF-α - IFN-γ cytokine levels, and impaired cytotoxic capacity (evidenced by increased cell proliferation and elevated HBVsvp levels in co-cultures with HepG2.2.15 cells in a time-dependent), relative to healthy donors. Conclusion These findings suggest that HBVsvp may induce dysfunctional NK cell responses characterized by phenotypic imbalance with subsequent reduction in cytokine and cytotoxic levels, indicating HBVsvp immunosuppressive effect that compromises antiviral defense in CHB patients. These data enhance our understanding of NK cell interactions with HBsAg and highlight the potential for targeting CD94 inhibitory receptors to restore NK cell function as an immunotherapeutic approach. Further clinical research is needed to validate these observations and establish their utility as reliable biomarkers.
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Affiliation(s)
- Mohamed A Selim
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Reda A Suef
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Ebrahim Saied
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Mostafa A Abdel-Maksoud
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Saeedah Musaed Almutairi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Aufy
- Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
| | - Adel A Mousa
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Mohamed T M Mansour
- Virology and Immunology Department, National Cancer Institute, Cairo University and Childern's Cancer Hospital, Cairo, Egypt
| | - Mohamed M S Farag
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
- Biomedical Research Department, Armed Forces College of Medicine (AFCM), Cairo, Egypt
- The Regional Centre for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt
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Sokolov D, Gorshkova A, Tyshchuk E, Grebenkina P, Zementova M, Kogan I, Totolian A. Large Extracellular Vesicles Derived from Natural Killer Cells Affect the Functions of Monocytes. Int J Mol Sci 2024; 25:9478. [PMID: 39273424 PMCID: PMC11395174 DOI: 10.3390/ijms25179478] [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: 06/03/2024] [Revised: 08/13/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Communication between natural killer cells (NK cells) and monocytes/macrophages may play an important role in immunomodulation and regulation of inflammatory processes. The aim of this research was to investigate the impact of NK cell-derived large extracellular vesicles on monocyte function because this field is understudied. We studied how NK-cell derived large extracellular vesicles impact on THP-1 cells characteristics after coculturing: phenotype, functions were observed with flow cytometry. In this study, we demonstrated the ability of large extracellular vesicles produced by NK cells to integrate into the membranes of THP-1 cells and influence the viability, phenotype, and functional characteristics of the cells. The results obtained demonstrate the ability of large extracellular vesicles to act as an additional component in the immunomodulatory activity of NK cells in relation to monocytes.
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Affiliation(s)
- Dmitry Sokolov
- Federal State Budgetary Scientific Institution "The Research Institute of Obstetrics, Gynecology and Reproductology Named after D.O. Ott", 199034 St. Petersburg, Russia
- Saint-Petersburg Pasteur Institute, 197101 St. Petersburg, Russia
| | - Alina Gorshkova
- Federal State Budgetary Scientific Institution "The Research Institute of Obstetrics, Gynecology and Reproductology Named after D.O. Ott", 199034 St. Petersburg, Russia
| | - Elizaveta Tyshchuk
- Federal State Budgetary Scientific Institution "The Research Institute of Obstetrics, Gynecology and Reproductology Named after D.O. Ott", 199034 St. Petersburg, Russia
- Saint-Petersburg Pasteur Institute, 197101 St. Petersburg, Russia
| | - Polina Grebenkina
- Federal State Budgetary Scientific Institution "The Research Institute of Obstetrics, Gynecology and Reproductology Named after D.O. Ott", 199034 St. Petersburg, Russia
- Saint-Petersburg Pasteur Institute, 197101 St. Petersburg, Russia
| | - Maria Zementova
- Federal State Budgetary Scientific Institution "The Research Institute of Obstetrics, Gynecology and Reproductology Named after D.O. Ott", 199034 St. Petersburg, Russia
- Saint-Petersburg Pasteur Institute, 197101 St. Petersburg, Russia
| | - Igor Kogan
- Federal State Budgetary Scientific Institution "The Research Institute of Obstetrics, Gynecology and Reproductology Named after D.O. Ott", 199034 St. Petersburg, Russia
| | - Areg Totolian
- Saint-Petersburg Pasteur Institute, 197101 St. Petersburg, Russia
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7
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Wang P, Zheng Y, Sun J, Zhang Y, Chan WK, Lu Y, Li X, Yang Z, Wang Y. Sepsis induced dysfunction of liver type 1 innate lymphoid cells. BMC Immunol 2024; 25:57. [PMID: 39210270 PMCID: PMC11363412 DOI: 10.1186/s12865-024-00648-6] [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: 03/05/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Sepsis is a life-threatening condition triggered by uncontrolled immune responses to infection, leading to widespread inflammation, tissue damage, organ dysfunction, and potentially death. The liver plays a crucial role in the immune response during sepsis, serving as a major site for immune cell activation and cytokine production. Liver type 1 innate lymphoid cells (ILCs) consist of NK cells and ILC1s. They maintain the local immune microenvironment by directly eliminating target cells and secreting cytokines. However, the specific roles and pathological changes of liver-resident NK cells and ILC1s during sepsis remain poorly understood. RESULTS This study aims to investigate the pathological changes of NK cells and ILC1s, which might contribute the dysfunction of liver. Sepsis mouse model was established by cecal ligation and puncture (CLP). Mouse immune cells from liver were isolated, and the surface makers, gene expression profiles, cytokine response and secretion, and mitochondrial function of NK (Natural Killer) cells and ILC1s (Innate Lymphoid Cell 1) were analyzed. A significant decrease in the number of mature NK cells was observed in the liver after CLP. Furthermore, the secretion of interferon-gamma (IFN-γ) was found to be reduced in spleen and liver NK cells when stimulated by IL-18. Mitochondrial activities in both liver NK cells and ILC1 were found to be increased during sepsis, suggesting an enhanced metabolic response in these cells to combat the infection. However, despite this heightened activity, liver NK cells exhibited a decreased level of cytotoxicity, which might impact their ability to target infected cells effectively. RNA sequencing supported and provided the potential mechanisms for the proinflammatory effects and exhaustion like phenotypes of liver NK cells. CONCLUSIONS Sepsis induces dysfunction and exhaustion-like phenotypes in liver NK cells and ILC1, which might further impair other immune cells and represent a potential therapeutic target for sepsis.
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Affiliation(s)
- Peiying Wang
- Institute of Medical Engineering & Translational Medicine, Tianjin University, 92 Weijin Road, Tianjin, 300072, China
| | - Yiran Zheng
- Institute of Medical Engineering & Translational Medicine, Tianjin University, 92 Weijin Road, Tianjin, 300072, China
| | - Jiaman Sun
- Institute of Medical Engineering & Translational Medicine, Tianjin University, 92 Weijin Road, Tianjin, 300072, China
| | - Yumo Zhang
- Institute of Medical Engineering & Translational Medicine, Tianjin University, 92 Weijin Road, Tianjin, 300072, China
| | - Wing Keung Chan
- Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, 43210, USA
| | - Yan Lu
- Zhejiang Provincial Key Lab of Geriatrics and Geriatrics Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, 1229 Gudun Road, Hangzhou, 310030, China
| | - Xiaohong Li
- Institute of Medical Engineering & Translational Medicine, Tianjin University, 92 Weijin Road, Tianjin, 300072, China.
| | - Zhouxin Yang
- Zhejiang Provincial Key Lab of Geriatrics and Geriatrics Institute of Zhejiang Province, Department of Geriatrics, Zhejiang Hospital, 1229 Gudun Road, Hangzhou, 310030, China.
| | - Youwei Wang
- Institute of Medical Engineering & Translational Medicine, Tianjin University, 92 Weijin Road, Tianjin, 300072, China.
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8
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Yang S, Guo J, Xiong Y, Han G, Luo T, Peng S, Liu J, Hu T, Zha Y, Lin X, Tan Y, Zhang J. Unraveling the genetic and molecular landscape of sepsis and acute kidney injury: A comprehensive GWAS and machine learning approach. Int Immunopharmacol 2024; 137:112420. [PMID: 38851159 DOI: 10.1016/j.intimp.2024.112420] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/29/2024] [Accepted: 06/03/2024] [Indexed: 06/10/2024]
Abstract
OBJECTIVES This study aimed to explore the underlying mechanisms of sepsis and acute kidney injury (AKI), including sepsis-associated AKI (SA-AKI), a frequent complication in critically ill sepsis patients. METHODS GWAS data was analyzed for genetic association between AKI and sepsis. Then, we systematically applied three distinct machine learning algorithms (LASSO, SVM-RFE, RF) to rigorously identify and validate signature genes of SA-AKI, assessing their diagnostic and prognostic value through ROC curves and survival analysis. The study also examined the functional and immunological aspects of these genes, potential drug targets, and ceRNA networks. A mouse model of sepsis was created to test the reliability of these signature genes. RESULTS LDSC confirmed a positive genetic correlation between AKI and sepsis, although no significant shared loci were found. Bidirectional MR analysis indicated mutual increased risks of AKI and sepsis. Then, 311 key genes common to sepsis and AKI were identified, with 42 significantly linked to sepsis prognosis. Six genes, selected through LASSO, SVM-RFE, and RF algorithms, showed excellent predictive performance for sepsis, AKI, and SA-AKI. The models demonstrated near-perfect AUCs in both training and testing datasets, and a perfect AUC in a sepsis mouse model. Significant differences in immune cells, immune-related pathways, HLA, and checkpoint genes were found between high- and low-risk groups. The study identified 62 potential drug treatments for sepsis and AKI and constructed a ceRNA network. CONCLUSIONS The identified signature genes hold potential clinical applications, including prognostic evaluation and targeted therapeutic strategies for sepsis and AKI. However, further research is needed to confirm these findings.
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Affiliation(s)
- Sha Yang
- Guizhou University Medical College, Guiyang 550025, Guizhou Province, China
| | - Jing Guo
- Guizhou University Medical College, Guiyang 550025, Guizhou Province, China
| | - Yunbiao Xiong
- Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, China
| | - Guoqiang Han
- Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, China
| | - Tao Luo
- Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, China
| | - Shuo Peng
- Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, China
| | - Jian Liu
- Guizhou University Medical College, Guiyang 550025, Guizhou Province, China; Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, China
| | - Tieyi Hu
- Department of Neurology, the Affiliated Dazu Hospital of Chongqing Medical University , China
| | - Yan Zha
- Guizhou University Medical College, Guiyang 550025, Guizhou Province, China; Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Xin Lin
- Department of Nephrology, Guizhou Provincial People's Hospital, Guiyang, China.
| | - Ying Tan
- Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, China.
| | - Jiqin Zhang
- Department of Anesthesiology, Guizhou Provincial People's Hospital, Guiyang, China.
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9
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Wang W, Ma L, Liu B, Ouyang L. The role of trained immunity in sepsis. Front Immunol 2024; 15:1449986. [PMID: 39221248 PMCID: PMC11363069 DOI: 10.3389/fimmu.2024.1449986] [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: 06/16/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
Sepsis is defined as a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection, characterized by a systemic inflammatory response to infection. The use of antibiotics, fluid resuscitation, and organ support therapy has limited prognostic benefit in patients with sepsis, and its incidence is not diminishing, which is attracting increased attention in medicine. Sepsis remains one of the most debilitating and expensive illnesses. One of the main reasons of septic mortality is now understood to be disruption of immune homeostasis. Immunotherapy is revolutionizing the treatment of illnesses in which dysregulated immune responses play a significant role. This "trained immunity", which is a potent defense against infection regardless of the type of bacteria, fungus, or virus, is attributed to the discovery that the innate immune cells possess immune memory via metabolic and epigenetic reprogramming. Here we reviewed the immunotherapy of innate immune cells in sepsis, the features of trained immunity, and the relationship between trained immunity and sepsis.
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Affiliation(s)
| | | | | | - Liangliang Ouyang
- Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
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10
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Roychowdhury S, Pant B, Cross E, Scheraga R, Vachharajani V. Effect of ethanol exposure on innate immune response in sepsis. J Leukoc Biol 2024; 115:1029-1041. [PMID: 38066660 PMCID: PMC11136611 DOI: 10.1093/jleuko/qiad156] [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: 05/10/2023] [Revised: 11/08/2023] [Accepted: 11/17/2023] [Indexed: 01/06/2024] Open
Abstract
Alcohol use disorder, reported by 1 in 8 critically ill patients, is a risk factor for death in sepsis patients. Sepsis, the leading cause of death, kills over 270,000 patients in the United States alone and remains without targeted therapy. Immune response in sepsis transitions from an early hyperinflammation to persistent inflammation and immunosuppression and multiple organ dysfunction during late sepsis. Innate immunity is the first line of defense against pathogen invasion. Ethanol exposure is known to impair innate and adaptive immune response and bacterial clearance in sepsis patients. Specifically, ethanol exposure is known to modulate every aspect of innate immune response with and without sepsis. Multiple molecular mechanisms are implicated in causing dysregulated immune response in ethanol exposure with sepsis, but targeted treatments have remained elusive. In this article, we outline the effects of ethanol exposure on various innate immune cell types in general and during sepsis.
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Affiliation(s)
- Sanjoy Roychowdhury
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Bishnu Pant
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Emily Cross
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Rachel Scheraga
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
- Department of Pulmonary and Critical Care Medicine, Integrated Hospital-Care Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195, United States
| | - Vidula Vachharajani
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
- Department of Pulmonary and Critical Care Medicine, Integrated Hospital-Care Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195, United States
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11
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Cajander S, Kox M, Scicluna BP, Weigand MA, Mora RA, Flohé SB, Martin-Loeches I, Lachmann G, Girardis M, Garcia-Salido A, Brunkhorst FM, Bauer M, Torres A, Cossarizza A, Monneret G, Cavaillon JM, Shankar-Hari M, Giamarellos-Bourboulis EJ, Winkler MS, Skirecki T, Osuchowski M, Rubio I, Bermejo-Martin JF, Schefold JC, Venet F. Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine. THE LANCET. RESPIRATORY MEDICINE 2024; 12:305-322. [PMID: 38142698 DOI: 10.1016/s2213-2600(23)00330-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 08/14/2023] [Accepted: 08/24/2023] [Indexed: 12/26/2023]
Abstract
Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes.
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Affiliation(s)
- Sara Cajander
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Matthijs Kox
- Department of Intensive Care Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
| | - Brendon P Scicluna
- Department of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei hospital, University of Malta, Msida, Malta; Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
| | - Markus A Weigand
- Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Raquel Almansa Mora
- Department of Cell Biology, Genetics, Histology and Pharmacology, University of Valladolid, Valladolid, Spain
| | - Stefanie B Flohé
- Department of Trauma, Hand, and Reconstructive Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ignacio Martin-Loeches
- St James's Hospital, Dublin, Ireland; Hospital Clinic, Institut D'Investigacions Biomediques August Pi i Sunyer, Universidad de Barcelona, Barcelona, Spain
| | - Gunnar Lachmann
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Operative Intensive Care Medicine, Berlin, Germany
| | - Massimo Girardis
- Department of Intensive Care and Anesthesiology, University Hospital of Modena, Modena, Italy
| | - Alberto Garcia-Salido
- Hospital Infantil Universitario Niño Jesús, Pediatric Critical Care Unit, Madrid, Spain
| | - Frank M Brunkhorst
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Michael Bauer
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Antoni Torres
- Pulmonology Department. Hospital Clinic of Barcelona, University of Barcelona, Ciberes, IDIBAPS, ICREA, Barcelona, Spain
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Guillaume Monneret
- Immunology Laboratory, Hôpital E Herriot - Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon-1, Hôpital E Herriot, Lyon, France
| | | | - Manu Shankar-Hari
- Centre for Inflammation Research, Institute of Regeneration and Repair, The University of Edinburgh, Edinburgh, UK
| | | | - Martin Sebastian Winkler
- Department of Anesthesiology and Intensive Care, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Tomasz Skirecki
- Department of Translational Immunology and Experimental Intensive Care, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Marcin Osuchowski
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
| | - Ignacio Rubio
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Jesus F Bermejo-Martin
- Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain; School of Medicine, Universidad de Salamanca, Salamanca, Spain; Centro de Investigación Biomédica en Red en Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
| | - Joerg C Schefold
- Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Fabienne Venet
- Immunology Laboratory, Hôpital E Herriot - Hospices Civils de Lyon, Lyon, France; Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Ecole Normale Supeérieure de Lyon, Universiteé Claude Bernard-Lyon 1, Lyon, France.
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Santacroce E, D’Angerio M, Ciobanu AL, Masini L, Lo Tartaro D, Coloretti I, Busani S, Rubio I, Meschiari M, Franceschini E, Mussini C, Girardis M, Gibellini L, Cossarizza A, De Biasi S. Advances and Challenges in Sepsis Management: Modern Tools and Future Directions. Cells 2024; 13:439. [PMID: 38474403 PMCID: PMC10931424 DOI: 10.3390/cells13050439] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 02/27/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Sepsis, a critical condition marked by systemic inflammation, profoundly impacts both innate and adaptive immunity, often resulting in lymphopenia. This immune alteration can spare regulatory T cells (Tregs) but significantly affects other lymphocyte subsets, leading to diminished effector functions, altered cytokine profiles, and metabolic changes. The complexity of sepsis stems not only from its pathophysiology but also from the heterogeneity of patient responses, posing significant challenges in developing universally effective therapies. This review emphasizes the importance of phenotyping in sepsis to enhance patient-specific diagnostic and therapeutic strategies. Phenotyping immune cells, which categorizes patients based on clinical and immunological characteristics, is pivotal for tailoring treatment approaches. Flow cytometry emerges as a crucial tool in this endeavor, offering rapid, low cost and detailed analysis of immune cell populations and their functional states. Indeed, this technology facilitates the understanding of immune dysfunctions in sepsis and contributes to the identification of novel biomarkers. Our review underscores the potential of integrating flow cytometry with omics data, machine learning and clinical observations to refine sepsis management, highlighting the shift towards personalized medicine in critical care. This approach could lead to more precise interventions, improving outcomes in this heterogeneously affected patient population.
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Affiliation(s)
- Elena Santacroce
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Miriam D’Angerio
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Alin Liviu Ciobanu
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Linda Masini
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Domenico Lo Tartaro
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Irene Coloretti
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Stefano Busani
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Ignacio Rubio
- Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany;
| | - Marianna Meschiari
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Erica Franceschini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Cristina Mussini
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Massimo Girardis
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy; (I.C.); (S.B.); (M.M.); (E.F.); (C.M.); (M.G.)
| | - Lara Gibellini
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
| | - Sara De Biasi
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy; (E.S.); (M.D.); (A.L.C.); (L.M.); (D.L.T.); (L.G.); (A.C.)
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Carcillo JA, Shakoory B. Cytokine Storm and Sepsis-Induced Multiple Organ Dysfunction Syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:441-457. [PMID: 39117832 DOI: 10.1007/978-3-031-59815-9_30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
There is extensive overlap of clinical features among familial or primary HLH (pHLH), reactive or secondary hemophagocytic lymphohistiocytosis (sHLH) [including macrophage activation syndrome (MAS) related to rheumatic diseases], and hyperferritinemic sepsis-induced multiple organ dysfunction syndrome (MODS); however, the distinctive pathobiology that causes hyperinflammatory process in each condition requires careful considerations for therapeutic decision-making. pHLH is defined by five or more of eight HLH-2004 criteria [1], where genetic impairment of natural killer (NK) cells or CD8+ cytolytic T cells results in interferon gamma (IFN-γ)-induced hyperinflammation regardless of triggering factors. Cytolytic treatments (e.g., etoposide) or anti-IFN-γ monoclonal antibody (emapalumab) has been effectively used to bridge the affected patients to hematopoietic stem cell transplant. Secondary forms of HLH also have normal NK cell number with decreased cytolytic function of varying degrees depending on the underlying and triggering factors. Although etoposide was uniformly used in sHLH/MAS in the past, the treatment strategy in different types of sHLH/MAS is increasingly streamlined to reflect the triggering/predisposing conditions, severity/progression, and comorbidities. Accordingly, in hyperferritinemic sepsis, the combination of hepatobiliary dysfunction (HBD) and disseminated intravascular coagulation (DIC) reflects reticuloendothelial system dysfunction and defines sepsis-associated MAS. It is demonstrated that as the innate immune response to infectious organism prolongs, it results in reduction in T cells and NK cells with subsequent lymphopenia even though normal cytolytic activity continues (Figs. 30.1, 30.2, 30.3, and 30.4). These changes allow free hemoglobin and pathogens to stimulate inflammasome activation in the absence of interferon-γ (IFN-γ) production that often responds to source control, intravenous immunoglobulin (IVIg), plasma exchange, and interleukin 1 receptor antagonist (IL-1Ra), similar to non-EBV, infection-induced HLH.
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Affiliation(s)
- Joseph A Carcillo
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Bita Shakoory
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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King HAD, Pokkali S, Kim D, Brammer D, Song K, McCarthy E, Lehman C, Todd JP, Foulds KE, Darrah PA, Seder RA, Bolton DL, Roederer M. Immune Activation Profiles Elicited by Distinct, Repeated TLR Agonist Infusions in Rhesus Macaques. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1643-1655. [PMID: 37861342 PMCID: PMC10656433 DOI: 10.4049/jimmunol.2300424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/28/2023] [Indexed: 10/21/2023]
Abstract
TLR agonists are a promising class of immune system stimulants investigated for immunomodulatory applications in cancer immunotherapy and viral diseases. In this study, we sought to characterize the safety and immune activation achieved by different TLR agonists in rhesus macaques (Macaca mulatta), a useful preclinical model of complex immune interactions. Macaques received one of three TLR agonists, followed by plasma cytokine, immune cell subset representation, and blood cell activation measurements. The TLR4 agonist LPS administered i.v. induced very transient immune activation, including TNF-α expression and monocyte activation. The TLR7/8 agonist 2BXy elicited more persistent cytokine expression, including type I IFN, IL-1RA, and the proinflammatory IL-6, along with T cell and monocyte activation. Delivery of 2BXy i.v. and i.m. achieved comparable immune activation, which increased with escalating dose. Finally, i.v. bacillus Calmette-Guérin (BCG) vaccination (which activates multiple TLRs, especially TLR2/4) elicited the most pronounced and persistent innate and adaptive immune response, including strong induction of IFN-γ, IL-6, and IL-1RA. Strikingly, monocyte, T cell, and NK cell expression of the proliferation marker Ki67 increased dramatically following BCG vaccination. This aligned with a large increase in total and BCG-specific cells measured in the lung. Principal component analysis of the combined cytokine expression and cellular activation responses separated animals by treatment group, indicating distinct immune activation profiles induced by each agent. In sum, we report safe, effective doses and routes of administration for three TLR agonists that exhibit discrete immunomodulatory properties in primates and may be leveraged in future immunotherapeutic strategies.
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Affiliation(s)
- Hannah A. D. King
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD
| | - Supriya Pokkali
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | - Dohoon Kim
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD
| | - Daniel Brammer
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | - Kaimei Song
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | | | - Chelsea Lehman
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | - John-Paul Todd
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | - Kathryn E. Foulds
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | | | - Robert A. Seder
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | - Diane L. Bolton
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD
| | - Mario Roederer
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
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Mestre-Durán C, Martín-Cortázar C, García-Solís B, Pernas A, Pertíñez L, Galán V, Sisinni L, Clares-Villa L, Navarro-Zapata A, Al-Akioui K, Escudero A, Ferreras C, Pérez-Martínez A. Ruxolitinib does not completely abrogate the functional capabilities of TLR4/9 ligand-activated NK cells. Front Immunol 2023; 13:1045316. [PMID: 36685552 PMCID: PMC9851469 DOI: 10.3389/fimmu.2022.1045316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023] Open
Abstract
Introduction Natural killer (NK) cells are lymphocytes from the innate immune system part of the first defense barrier against infected and transformed cells, representing 5%-15% of peripheral blood lymphocytes. The cytotoxic capacity of NK cells is controlled by a balance between inhibitory and activating NK receptors expressed on their surface, which recognize and interact with the ligands on stressed cells. The cytokines involved in NK cell activation, proliferation, survival, and cytotoxicity are signaled mainly through the Janus kinase and signal transducer and activator of transcription proteins (JAK/STAT) pathway. NK cells are also activated in response to pathogens through Toll-like receptors (TLRs) expressed on their surface. Ruxolitinib is a specific JAK1/2 inhibitor approved for treating myelofibrosis and for steroid-refractory acute and chronic graft-versus-host disease (SR-GvHD). Methods Purified NK cells from healthy donors were stimulated with two TOLL-like receptor ligands, LPS and CpG, in the presence of different concentrations of Ruxolitinib. Results This study showed the effects of ruxolitinib on TLR4 and TLR9 ligand-activated NK cells from healthy donors. Ruxolitinib did not completely inhibit STAT3 phosphorylation and had a moderate effect on NK cell cytokine activation via the TLR pathway. Only the highest doses of ruxolitinib led to a decrease in the pro-inflammatory cytokines tumor necrosis factor α, interferon-γ, interleukin-6, and interleukin-1β. The cytotoxic capacity of stimulated NK cells versus K562, SEM, and MV-4-11 cell lines was reduced by increasing doses of ruxolitinib, but it was not completely abolished and we observed no major changes in degranulation capacity. Phenotypic changes were observed in activated NK cells in the presence of ruxolitinib. In a small cohort of pediatric patients treated with ruxolitinib for SR-GvHD, we observed no decrease in NK cell counts; however, further prospective studies with larger cohorts are necessary to confirm this finding. Discussion In summary, our results showed that the functional capabilities and phenotype of NK cells activated through TLR4/9 agonists were not completely abolished by the inhibition of the JAK-STAT pathway by ruxolitinib.
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Affiliation(s)
- Carmen Mestre-Durán
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Carla Martín-Cortázar
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Blanca García-Solís
- Laboratory of Immunogenetics of Human Diseases, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Alicia Pernas
- Department of Genetics, Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain
| | - Lidia Pertíñez
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Víctor Galán
- Pediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain
| | - Luisa Sisinni
- Pediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain
| | - Laura Clares-Villa
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Alfonso Navarro-Zapata
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Karima Al-Akioui
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Adela Escudero
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
- Department of Genetics, Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain
| | - Cristina Ferreras
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
| | - Antonio Pérez-Martínez
- Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
- Pediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain
- Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain
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Cheng Y, Xu L, Wang J, Cao X, Chen D, Zhang P, Yang L, Qin L. Analysis of bulk RNA-seq data from sepsis patients reveals sepsis-associated lncRNAs and targeted cell death-related genes contributing to immune microenvironment regulation. Front Immunol 2023; 14:1026086. [PMID: 36817490 PMCID: PMC9932711 DOI: 10.3389/fimmu.2023.1026086] [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: 08/23/2022] [Accepted: 01/25/2023] [Indexed: 02/05/2023] Open
Abstract
Background Sepsis is a life-threatening organ dysfunction syndrome that leads to the massive death of immune cells. Long non-coding RNAs (lncRNAs) have been reported to exert key regulatory roles in cells. However, it is unclear how lncRNAs regulate the survival of immune cells in the occurrence and development of sepsis. Methods In this study, we used blood whole transcriptome sequencing data (RNA-seq) from normal controls (Hlty) and patients with uncomplicated infection (Inf1 P), sepsis (Seps P), and septic shock (Shock P), to investigate the fraction changes of immune cell types, expression pattern of cell death-related genes, as well as differentially expressed lncRNAs. Association network among these factors was constructed to screen out essential immune cell types, lncRNAs and their potential targets. Finally, the expression of lncRNAs and cell death genes in sepsis patients were validated by qRT-PCR. Results In this study, we found fifteen immune cell types showed significant fraction difference between Hlty and three patient groups. The expression pattern of cell death-related genes was also dysregulated in Hlty compared with patient groups. Co-expression network analysis identified a key turquoise module that was associated with the fraction changes of immune cells. We then identified differentially expressed lncRNAs and their potential targets that were tightly associated with the immune cell dysregulation in sepsis. Seven lncRNAs, including LINC00861, LINC01278, RARA-AS1, RP11-156P1.3, RP11-264B17.3, RP11-284N8.3 and XLOC_011309, as well as their co-expressed cell death genes, were finally identified, and we validated two lncRNAs (LINC00861 and LINC01278) and four mRNA targets using qRT-PCR in sepsis samples. Conclusion The global analysis of cell death-related genes in the occurrence and development of sepsis was carried out for the first time, and its expression regulation mode was displayed. The expression pattern of sepsis-associated lncRNAs were analyzed and identified, and the lncRNAs were significantly related to the change of immune cell proportion. We highlight the important roles of lncRNAs and their potential targets in the regulation of immune cell fraction changes during sepsis progression. The identified lncRNAs and their target genes may become new biomarkers and therapeutic targets of sepsis.
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Affiliation(s)
- Yanwei Cheng
- Department of Emergency, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Lijun Xu
- Department of Emergency, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Jiaoyang Wang
- Department of Emergency, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Xue Cao
- Department of Rheumatology and Immunology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Dong Chen
- Wuhan Ruixing Biotechnology Co., Ltd, Wuhan, China
| | - Peirong Zhang
- Department of Emergency, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Lei Yang
- Department of Emergency, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
| | - Lijie Qin
- Department of Emergency, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, China
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Karimi A, Pourreza S, Vajdi M, Mahmoodpoor A, Sanaie S, Karimi M, Tarighat-Esfanjani A. Evaluating the effects of curcumin nanomicelles on clinical outcome and cellular immune responses in critically ill sepsis patients: A randomized, double-blind, and placebo-controlled trial. Front Nutr 2022; 9:1037861. [PMID: 36562037 PMCID: PMC9763722 DOI: 10.3389/fnut.2022.1037861] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Introduction In sepsis, the immune system is overreacting to infection, leading to organ dysfunction and death. The purpose of this study was to investigate the impacts of curcumin nanomicelles on clinical outcomes and cellular immune responses in critically ill sepsis patients. Method For 10 days, 40 patients in the intensive care units (ICU) were randomized between the nano curcumin (NC) and placebo groups in a randomized study. We evaluated serum levels of biochemical factors, inflammatory biomarkers, the mRNA expression levels of FOXP3, NLRP-3, IFN-γ, and NF-κp genes in the PBMCs, and clinical outcomes before the beginning of the supplementation and on days 5 and 10. Results NLR family pyrin domain containing 3 (NLRP3), interferon gamma (IFN-γ), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mRNA expression levels significantly P = 0.014, P = 0.014, and P = 0.019, respectively) decreased, but forkhead box P3 (FOXP3) mRNA expression levels increased significantly (P = 0.008) in the NC group compared to the placebo group after 10 days. NC supplementation decreased serum levels of IL-22, IL-17, and high mobility group box 1 (HMGB1) (P < 0.05). Nevertheless, biochemical factors and nutritional status did not differ significantly (P > 0.05). NC supplementation resulted in decreased sequential organ failure assessment and multiple organ dysfunction syndromes scores, while it did not have significant impacts on length of stay in the ICU, systolic blood pressure, diastolic blood pressure, a saturation of oxygen (%), and respiratory rate (breaths/min) PaO2/FiO2 (p > 0.05). Conclusion For critically ill patients with sepsis, NC supplementation may be an effective therapeutic strategy. More randomized clinical trials involving longer follow-up periods and different doses are needed to achieve the best results.
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Affiliation(s)
- Arash Karimi
- Department of Clinical Nutrition, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Nutrition Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanaz Pourreza
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Vajdi
- Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ata Mahmoodpoor
- Department of Anesthesiology and Intensive Care, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sarvin Sanaie
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mozhde Karimi
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran
| | - Ali Tarighat-Esfanjani
- Department of Clinical Nutrition, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Nutrition Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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Gondoh E, Hamada Y, Mori T, Iwazawa Y, Shinohara A, Narita M, Sato D, Tezuka H, Yamauchi T, Tsujimura M, Yoshida S, Tanaka K, Yamashita K, Akatori H, Higashiyama K, Arakawa K, Suda Y, Miyano K, Iseki M, Inada E, Kuzumaki N, Narita M. Possible mechanism for improving the endogenous immune system through the blockade of peripheral μ-opioid receptors by treatment with naldemedine. Br J Cancer 2022; 127:1565-1574. [PMID: 35945243 PMCID: PMC9553910 DOI: 10.1038/s41416-022-01928-x] [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: 12/31/2021] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND It has been considered that activation of peripheral μ-opioid receptors (MORs) induces side effects of opioids. In this study, we investigated the possible improvement of the immune system in tumour-bearing mice by systemic administration of the peripheral MOR antagonist naldemedine. METHODS The inhibitory effect of naldemedine on MOR-mediated signalling was tested by cAMP inhibition and β-arrestin recruitment assays using cultured cells. We assessed possible changes in tumour progression and the number of splenic lymphocytes in tumour-bearing mice under the repeated oral administration of naldemedine. RESULTS Treatment with naldemedine produced a dose-dependent inhibition of both the decrease in the cAMP level and the increase in β-arrestin recruitment induced by the MOR agonists. Repeated treatment with naldemedine at a dose that reversed the morphine-induced inhibition of gastrointestinal transport, but not antinociception, significantly decreased tumour volume and prolonged survival in tumour-transplanted mice. Naldemedine administration significantly decreased the increased expression of immune checkpoint-related genes and recovered the decreased level of toll-like receptor 4 in splenic lymphocytes in tumour-bearing mice. CONCLUSIONS The blockade of peripheral MOR may induce an anti-tumour effect through the recovery of T-cell exhaustion and promotion of the tumour-killing system.
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Affiliation(s)
- Eizoh Gondoh
- Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Yusuke Hamada
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tomohisa Mori
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Yusuke Iwazawa
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Asami Shinohara
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Michiko Narita
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Daisuke Sato
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hiroyuki Tezuka
- Department of Cellular Function Analysis, Research Promotion Headquarters, Fujita Health University, Aichi, Japan
| | - Takayasu Yamauchi
- Institute of Medicinal Chemistry, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Mayu Tsujimura
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Sara Yoshida
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Kenichi Tanaka
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Kensuke Yamashita
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Haruka Akatori
- Institute of Medicinal Chemistry, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Kimio Higashiyama
- Institute of Medicinal Chemistry, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Kazuhiko Arakawa
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Yukari Suda
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Kanako Miyano
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Masako Iseki
- Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Eiichi Inada
- Department of Anesthesiology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Naoko Kuzumaki
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
| | - Minoru Narita
- Department of Anesthesiology and Pain Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
- Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
- Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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Liu D, Huang SY, Sun JH, Zhang HC, Cai QL, Gao C, Li L, Cao J, Xu F, Zhou Y, Guan CX, Jin SW, Deng J, Fang XM, Jiang JX, Zeng L. Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options. Mil Med Res 2022; 9:56. [PMID: 36209190 PMCID: PMC9547753 DOI: 10.1186/s40779-022-00422-y] [Citation(s) in RCA: 200] [Impact Index Per Article: 66.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 09/27/2022] [Indexed: 12/02/2022] Open
Abstract
Sepsis is a common complication of combat injuries and trauma, and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is also one of the significant causes of death and increased health care costs in modern intensive care units. The use of antibiotics, fluid resuscitation, and organ support therapy have limited prognostic impact in patients with sepsis. Although its pathophysiology remains elusive, immunosuppression is now recognized as one of the major causes of septic death. Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis. It is characterized by the release of anti-inflammatory cytokines, abnormal death of immune effector cells, hyperproliferation of immune suppressor cells, and expression of immune checkpoints. By targeting immunosuppression, especially with immune checkpoint inhibitors, preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance. Here, we comprehensively discuss recent findings on the mechanisms, regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.
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Affiliation(s)
- Di Liu
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400042, China
| | - Si-Yuan Huang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400042, China
| | - Jian-Hui Sun
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400042, China
| | - Hua-Cai Zhang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400042, China
| | - Qing-Li Cai
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400042, China
| | - Chu Gao
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400042, China
| | - Li Li
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Ju Cao
- Department of Laboratory Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Fang Xu
- Department of Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Yong Zhou
- Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, China
| | - Cha-Xiang Guan
- Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, China
| | - Sheng-Wei Jin
- Department of Anesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, 325027, Wenzhou, China
| | - Jin Deng
- Department of Emergency, the Affiliated Hospital of Guizhou Medical University, Guizhou Medical University, 550001, Guiyang, China
| | - Xiang-Ming Fang
- Department of Anesthesiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China.
| | - Jian-Xin Jiang
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400042, China.
| | - Ling Zeng
- Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400042, China.
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20
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Warner K, Ghaedi M, Chung DC, Jacquelot N, Ohashi PS. Innate lymphoid cells in early tumor development. Front Immunol 2022; 13:948358. [PMID: 36032129 PMCID: PMC9411809 DOI: 10.3389/fimmu.2022.948358] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/26/2022] [Indexed: 12/20/2022] Open
Abstract
Innate and adaptive immune cells monitor, recognize, and eliminate transformed cells. Innate lymphoid cells (ILCs) are innate counterparts of T cells that play a key role in many facets of the immune response and have a profound impact on disease states, including cancer. ILCs regulate immune responses by responding and integrating a wide range of signals within the local microenvironment. As primarily tissue-resident cells, ILCs are ideally suited to sense malignant transformation and initiate anti-tumor immunity. However, as ILCs have been associated with anti-tumor and pro-tumor activities in established tumors, they could potentially have dual functions during carcinogenesis by promoting or suppressing the malignant outgrowth of premalignant lesions. Here we discuss emerging evidence that shows that ILCs can impact early tumor development by regulating immune responses against transformed cells, as well as the environmental cues that potentially induce ILC activation in premalignant lesions.
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Affiliation(s)
- Kathrin Warner
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Maryam Ghaedi
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Douglas C. Chung
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Nicolas Jacquelot
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Pamela S. Ohashi
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
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21
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Anderko RR, Gómez H, Canna SW, Shakoory B, Angus DC, Yealy DM, Huang DT, Kellum JA, Carcillo JA, Angus DC, Barnato AE, Eaton TL, Gimbel E, Huang DT, Keener C, Kellum JA, Landis K, Pike F, Stapleton DK, Weissfeld LA, Willochell M, Wofford KA, Yealy DM, Kulstad E, Watts H, Venkat A, Hou PC, Massaro A, Parmar S, Limkakeng AT, Brewer K, Delbridge TR, Mainhart A, Chawla LS, Miner JR, Allen TL, Grissom CK, Swadron S, Conrad SA, Carlson R, LoVecchio F, Bajwa EK, Filbin MR, Parry BA, Ellender TJ, Sama AE, Fine J, Nafeei S, Terndrup T, Wojnar M, Pearl RG, Wilber ST, Sinert R, Orban DJ, Wilson JW, Ufberg JW, Albertson T, Panacek EA, Parekh S, Gunn SR, Rittenberger JS, Wadas RJ, yEdwards AR, Kelly M, Wang HE, Holmes TM, McCurdy MT, Weinert C, Harris ES, Self WH, Phillips CA, Migues RM. Sepsis with liver dysfunction and coagulopathy predicts an inflammatory pattern of macrophage activation. Intensive Care Med Exp 2022; 10:6. [PMID: 35190900 PMCID: PMC8861227 DOI: 10.1186/s40635-022-00433-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 02/07/2022] [Indexed: 12/30/2022] Open
Abstract
Background Interleukin-1 receptor antagonists can reduce mortality in septic shock patients with hepatobiliary dysfunction and disseminated intravascular coagulation (HBD + DIC), an organ failure pattern with inflammatory features consistent with macrophage activation. Identification of clinical phenotypes in sepsis may allow for improved care. We aim to describe the occurrence of HBD + DIC in a contemporary cohort of patients with sepsis and determine the association of this phenotype with known macrophage activation syndrome (MAS) biomarkers and mortality. We performed a retrospective nested case–control study in adult septic shock patients with concurrent HBD + DIC and an equal number of age-matched controls, with comparative analyses of all-cause mortality and circulating biomarkers between the groups. Multiple logistic regression explored the effect of HBD + DIC on mortality and the discriminatory power of the measured biomarkers for HBD + DIC and mortality. Results Six percent of septic shock patients (n = 82/1341) had HBD + DIC, which was an independent risk factor for 90-day mortality (OR = 3.1, 95% CI 1.4–7.5, p = 0.008). Relative to sepsis controls, the HBD + DIC cohort had increased levels of 21 of the 26 biomarkers related to macrophage activation (p < 0.05). This panel was predictive of both HBD + DIC (sensitivity = 82%, specificity = 84%) and mortality (sensitivity = 92%, specificity = 90%). Conclusion The HBD + DIC phenotype identified patients with high mortality and a molecular signature resembling that of MAS. These observations suggest trials of MAS-directed therapies are warranted. Supplementary Information The online version contains supplementary material available at 10.1186/s40635-022-00433-y.
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22
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Qiu M, Zong JB, He QW, Liu YX, Wan Y, Li M, Zhou YF, Wu JH, Hu B. Cell Heterogeneity Uncovered by Single-Cell RNA Sequencing Offers Potential Therapeutic Targets for Ischemic Stroke. Aging Dis 2022; 13:1436-1454. [PMID: 36186129 PMCID: PMC9466965 DOI: 10.14336/ad.2022.0212] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 02/12/2022] [Indexed: 11/06/2022] Open
Abstract
Ischemic stroke is a detrimental neurological disease characterized by an irreversible infarct core surrounded by an ischemic penumbra, a salvageable region of brain tissue. Unique roles of distinct brain cell subpopulations within the neurovascular unit and peripheral immune cells during ischemic stroke remain elusive due to the heterogeneity of cells in the brain. Single-cell RNA sequencing (scRNA-seq) allows for an unbiased determination of cellular heterogeneity at high-resolution and identification of cell markers, thereby unveiling the principal brain clusters within the cell-type-specific gene expression patterns as well as cell-specific subclusters and their functions in different pathways underlying ischemic stroke. In this review, we have summarized the changes in differentiation trajectories of distinct cell types and highlighted the specific pathways and genes in brain cells that are impacted by stroke. This review is expected to inspire new research and provide directions for investigating the potential pathological mechanisms and novel treatment strategies for ischemic stroke at the level of a single cell.
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Affiliation(s)
| | | | | | | | | | | | | | - Jie-hong Wu
- Correspondence should be addressed to: Dr. Bo Hu () and Dr. Jie-hong Wu (), Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Hu
- Correspondence should be addressed to: Dr. Bo Hu () and Dr. Jie-hong Wu (), Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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Bi X, Yan X, Jiang B, Liang J, Zhou J, Lu S, Liu J, Luo L, Yin Z. Indoprofen exerts a potent therapeutic effect against sepsis by alleviating high mobility group box 1-mediated inflammatory responses. Toxicol Appl Pharmacol 2021; 433:115778. [PMID: 34755645 DOI: 10.1016/j.taap.2021.115778] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/23/2021] [Accepted: 10/25/2021] [Indexed: 01/07/2023]
Abstract
Indoprofen is a non-steroidal anti-inflammatory drug, and has provided insights into treatment of spinal muscular atrophies; however, the treatment effect of indoprofen on sepsis and the precise underlying mechanism remain to be elucidated. This study was carried out to examine the inhibitory effect of indoprofen on high mobility group box 1 (HMGB1)-mediated inflammatory responses in vivo and in vitro. Intraperitoneal injection of indoprofen (20 or 40 mg/kg) at 8 h post-sepsis markedly improved the survival of BALB/c mice and ameliorated multiple-organ injury by blocking the inflammatory responses. In addition, indoprofen partially reduced the HMGB1 level in the serum and in the lung, as well as ameliorated pulmonary edema. Mechanistically, indoprofen potently inhibited the release of HMGB1 following stimulation by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C), and suppressed recombinant human HMGB1(rhHMGB1)-induced inflammatory responses. It was also found that indoprofen has both cyclooxygenase 2-dependent and -independent inhibitory effects on the proinflammatory effect of HMGB1 in THP-1 cells. Further, the drug reduced rhHMGB1-induced cell surface levels of toll-like receptor 2, toll-like receptor 4, and receptor of advanced glycation end-products in a concentration-dependent manner. Collectively, these data demonstrated that the anti-inflammatory effect of indoprofen in sepsis was associated with HMGB1-mediated inflammatory responses, thus offering a favorable mechanistic basis to support the therapeutic potential of indoprofen for the treatment of lethal sepsis or other inflammatory diseases.
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Affiliation(s)
- Xiaowen Bi
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Xintong Yan
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Baolin Jiang
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Juanjuan Liang
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Jinyi Zhou
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Shuai Lu
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Jie Liu
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China
| | - Lan Luo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
| | - Zhimin Yin
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
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NK Cell Subpopulation Is Altered and the Expression of TLR1 and TLR9 Is Decreased in Patients with Acute Lymphoblastic Leukemia. JOURNAL OF ONCOLOGY 2021; 2021:5528378. [PMID: 34567117 PMCID: PMC8457960 DOI: 10.1155/2021/5528378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/28/2021] [Accepted: 08/05/2021] [Indexed: 11/20/2022]
Abstract
NK cells represent a heterogeneous subpopulation of lymphocytes of the innate immune system, which possess powerful antitumor activity. NK cells exhibit their function through a complex collection of receptors that act synergistically to recognize, regulate, or amplify the immune response. TLRs allow cells to detect PAMPs, MAMPs, or DAMPs, which are essential for the initiation of the immune response. Studies on the different subpopulations of NK cells and their expression profile of innate immune receptors in hematological cancers are limited. In this study, the specific subpopulations of NK cells in pediatric patients with acute lymphoblastic leukemia (ALL) and the repertoire and level of expression of TLRs in cytotoxic NK cells were assessed. The results suggested that pediatric patients with ALL exhibited a significant decrease in NK cells in peripheral blood and bone marrow, in addition to alterations in the distribution of the subpopulations of cells. Regulatory and cytotoxic NK cells were diminished, whereas dysfunctional phenotype was considerably increased. Cytotoxic NK cells from children with ALL expressed all 10 TLRs, and expression of TLR1 and TLR9 was decreased compared with the controls. Interestingly, cytotoxic NK cells exhibited a higher expression of TLR1 in the bone marrow than in the peripheral blood of patients with ALL. The present study is the first to show that TLR10 was expressed in the cytotoxic NK cells and the first to assess the profile and levels of the 10 known TLRs in cytotoxic NK cells from patients with ALL. The alterations in expression levels and cellular distribution may be involved in the immune response.
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25
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Durán-Laforet V, Peña-Martínez C, García-Culebras A, Alzamora L, Moro MA, Lizasoain I. Pathophysiological and pharmacological relevance of TLR4 in peripheral immune cells after stroke. Pharmacol Ther 2021; 228:107933. [PMID: 34174279 DOI: 10.1016/j.pharmthera.2021.107933] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/12/2021] [Accepted: 06/16/2021] [Indexed: 02/07/2023]
Abstract
Stroke is a very common disease being the leading cause of death and disability worldwide. The immune response subsequent to an ischemic stroke is a crucial factor in its physiopathology and outcome. This response is not limited to the injury site. In fact, the immune response to the ischemic process mobilizes mainly circulating cells which upon activation will be recruited to the injury site. When a stroke occurs, molecules that are usually retained inside the cell bodies are released into the extracellular space by uncontrolled cell death. These molecules can bind to the Toll-like receptor 4 (TLR4) in circulating immune cells which are then activated, eliciting, although not exclusively, the inflammatory response to the stroke. In this review, we present an up-to-date summary of the role of the different peripheral immune cells in stroke as well as the role of TLR4 in the function of each cell type in ischemia. Also, we summarize the different antagonists developed against TLR4 and their potential as a pharmacological tool for stroke treatment.
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Affiliation(s)
- V Durán-Laforet
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, Instituto de Investigación Hospital, 12 de Octubre (imas12), Madrid, Spain.
| | - C Peña-Martínez
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, Instituto de Investigación Hospital, 12 de Octubre (imas12), Madrid, Spain
| | - A García-Culebras
- Neurovascular Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
| | - L Alzamora
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, Instituto de Investigación Hospital, 12 de Octubre (imas12), Madrid, Spain
| | - M A Moro
- Neurovascular Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
| | - I Lizasoain
- Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, Instituto de Investigación Hospital, 12 de Octubre (imas12), Madrid, Spain.
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26
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Transient blockade of TBK1/IKKε allows efficient transduction of primary human natural killer cells with vesicular stomatitis virus G-pseudotyped lentiviral vectors. Cytotherapy 2021; 23:787-792. [PMID: 34119434 DOI: 10.1016/j.jcyt.2021.04.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 04/27/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AIMS Vesicular stomatitis virus G (VSV-G)-pseudotyped lentiviral vectors (LVs) are widely used to reliably generate genetically modified, clinical-grade T-cell products. However, the results of genetically modifying natural killer (NK) cells with VSV-G LVs have been variable. The authors explored whether inhibition of the IKK-related protein kinases TBK1 and IKKε, key signaling molecules of the endosomal TLR4 pathway, which is activated by VSV-G, would enable the reliable transduction of NK cells by VSV-G LVs. METHODS The authors activated NK cells from peripheral blood mononuclear cells using standard procedures and transduced them with VSV-G LVs encoding a marker gene (yellow fluorescent protein [YFP]) or functional genes (chimeric antigen receptors [CARs], co-stimulatory molecules) in the presence of three TBK1/IKKε inhibitors (MRT67307, BX-795, amlexanox). NK cell transduction was evaluated by flow cytometry and/or western blot and the functionality of expressed CARs was evaluated in vitro. RESULTS Blocking TBK1/IKKε during transduction of NK cells enabled their efficient transduction by VSV-G LVs as judged by YFPexpression of 40-50%, with half maximal effective concentrations of 1.1 µM (MRT67307), 5 µM (BX-795) and 24.8 µM (amlexanox). Focusing on MRT67307, the authors successfully generated NK cells expressing CD19-CARs or HER2-CARs with an inducible co-stimulatory molecule. CAR NK cells exhibited increased cytolytic activity and ability to produce cytokines in comparison to untreated controls, confirming CAR functionality. CONCLUSIONS The authors demonstrate that inhibition of TBK1/IKKε enables the reliable generation of genetically modified NK cells using VSV-G LVs. The authors' protocol can be readily adapted to generate clinical-grade NK cells and thus has the potential to facilitate the clinical evaluation of genetically modified NK cell-based therapeutics in the future.
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27
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Stolk RF, Reinema F, van der Pasch E, Schouwstra J, Bressers S, van Herwaarden AE, Gerretsen J, Schambergen R, Ruth M, van der Hoeven HG, van Leeuwen HJ, Pickkers P, Kox M. Phenylephrine impairs host defence mechanisms to infection: a combined laboratory study in mice and translational human study. Br J Anaesth 2021; 126:652-664. [PMID: 33483132 DOI: 10.1016/j.bja.2020.11.040] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/20/2020] [Accepted: 11/20/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Immunosuppression after surgery is associated with postoperative complications, mediated in part by catecholamines that exert anti-inflammatory effects via the β-adrenergic receptor. Phenylephrine, generally regarded as a selective α-adrenergic agonist, is frequently used to treat perioperative hypotension. However, phenylephrine may impair host defence through β-adrenergic affinity. METHODS Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and α- and β-adrenergic antagonists. C57BL/6J male mice received continuous infusion of phenylephrine (30-50 μg kg-1 min-1 i.v.) or saline via micro-osmotic pumps, before LPS administration (5 mg kg-1 i.v.) or caecal ligation and puncture (CLP). Twenty healthy males were randomised to a 5 h infusion of phenylephrine (0.5 μg kg-1 min-1) or saline before receiving LPS (2 ng kg-1 i.v.). RESULTS In vitro, phenylephrine enhanced LPS-induced production of the anti-inflammatory cytokine interleukin (IL)-10 (maximum augmentation of 93%) while attenuating the release of pro-inflammatory mediators. These effects were reversed by pre-incubation with β-antagonists, but not α-antagonists. Plasma IL-10 levels were higher in LPS-challenged mice infused with phenylephrine, whereas pro-inflammatory mediators were reduced. Phenylephrine infusion increased bacterial counts after CLP in peritoneal fluid (+42%, P=0.0069), spleen (+59%, P=0.04), and liver (+35%, P=0.09). In healthy volunteers, phenylephrine enhanced the LPS-induced IL-10 response (+76%, P=0.0008) while attenuating plasma concentrations of pro-inflammatory mediators including IL-8 (-15%, P=0.03). CONCLUSIONS Phenylephrine exerts potent anti-inflammatory effects, possibly involving the β-adrenoreceptor. Phenylephrine promotes bacterial outgrowth after surgical peritonitis. Phenylephrine may therefore compromise host defence in surgical patients and increase susceptibility towards infection. CLINICAL TRIAL REGISTRATION NCT02675868 (Clinicaltrials.gov).
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Affiliation(s)
- Roeland F Stolk
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Intensive Care Medicine, Hospital Rijnstate, Arnhem, The Netherlands
| | - Flavia Reinema
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Eva van der Pasch
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joost Schouwstra
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Steffi Bressers
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - Jelle Gerretsen
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Roel Schambergen
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mike Ruth
- Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hans G van der Hoeven
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Henk J van Leeuwen
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Intensive Care Medicine, Hospital Rijnstate, Arnhem, The Netherlands
| | - Peter Pickkers
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Matthijs Kox
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
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Rezasoltani S, Yadegar A, Asadzadeh Aghdaei H, Reza Zali M. Modulatory effects of gut microbiome in cancer immunotherapy: A novel paradigm for blockade of immune checkpoint inhibitors. Cancer Med 2021; 10:1141-1154. [PMID: 33369247 PMCID: PMC7897953 DOI: 10.1002/cam4.3694] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/26/2020] [Accepted: 12/06/2020] [Indexed: 12/12/2022] Open
Abstract
The human gastrointestinal (GI) tract harbors gut microbiome, which plays a crucial role in preserving homeostasis at the intestinal host-microbial interface. Conversely, specific gut microbiota may be altered during various pathological conditions and produce a number of toxic compounds and oncoproteins, in turn, to induce both inflammatory response and carcinogenesis. Recently, promising findings have been documented toward the implementation of certain intestinal microbiome in the next era of cancer biology and cancer immunotherapy. Notably, intestinal microbiota can cooperate with immune checkpoint inhibitors (ICIs) of its host, especially in enhancing the efficacy of programmed death 1 (PD-1) protein and its ligand programmed death ligand 1 (PD-L1) blockade therapy for cancer. Herein, we review the dual function of gut microbiota in triggering GI cancers, its association with host immunity and its beneficial functions in modulation of cancer immunotherapy responses. Furthermore, we consider the significance of gut microbiota as a potential biomarker for predicting the efficacy of cancer immunotherapy. Finally, we summarize the relevant limitations that affect the effectiveness and clinical applications of gut microbiome in response to immunotherapy.
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Affiliation(s)
- Sama Rezasoltani
- Foodborne and Waterborne Diseases Research CenterResearch Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research CenterResearch Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research CenterResearch Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research CenterResearch Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
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29
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Ma L, Li Q, Cai S, Peng H, Huyan T, Yang H. The role of NK cells in fighting the virus infection and sepsis. Int J Med Sci 2021; 18:3236-3248. [PMID: 34400893 PMCID: PMC8364442 DOI: 10.7150/ijms.59898] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 06/12/2021] [Indexed: 12/22/2022] Open
Abstract
Natural killer cells, one of the important types of innate immune cells, play a pivotal role in the antiviral process in vivo. It has been shown that increasing NK cell activity may promote the alleviation of viral infections, even severe infection-induced sepsis. Given the current state of the novel coronavirus (SARS-CoV-2) global pandemic, clarifying the anti-viral function of NK cells would be helpful for revealing the mechanism of host immune responses and decipher the progression of COVID-19 and providing important clues for combating this pandemic. In this review, we summarize the roles of NK cells in viral infection and sepsis as well as the potential possibilities of NK cell-based immunotherapy for treating COVID-19.
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Affiliation(s)
- Lu Ma
- The Hengyang Key Laboratory of Cellular Stress Biology, Institute of Cytology and Genetics, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Qi Li
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Suna Cai
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Hourong Peng
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Ting Huyan
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
| | - Hui Yang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China
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30
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Kim DO, Byun JE, Kim WS, Kim MJ, Choi JH, Kim H, Choi E, Kim TD, Yoon SR, Noh JY, Park YJ, Lee J, Cho HJ, Lee HG, Min SH, Choi I, Jung H. TXNIP Regulates Natural Killer Cell-Mediated Innate Immunity by Inhibiting IFN-γ Production during Bacterial Infection. Int J Mol Sci 2020; 21:ijms21249499. [PMID: 33327533 PMCID: PMC7765025 DOI: 10.3390/ijms21249499] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
The function of natural killer (NK) cell-derived interferon-γ (IFN-γ) expands to remove pathogens by increasing the ability of innate immune cells. Here, we identified the critical role of thioredoxin-interacting protein (TXNIP) in the production of IFN-γ in NK cells during bacterial infection. TXNIP inhibited the production of IFN-γ and the activation of transforming growth factor β-activated kinase 1 (TAK1) activity in primary mouse and human NK cells. TXNIP directly interacted with TAK1 and inhibited TAK1 activity by interfering with the complex formation between TAK1 and TAK1 binding protein 1 (TAB1). Txnip−/− (KO) NK cells enhanced the activation of macrophages by inducing IFN-γ production during Pam3CSK4 stimulation or Staphylococcus aureus (S. aureus) infection and contributed to expedite the bacterial clearance. Our findings suggest that NK cell-derived IFN-γ is critical for host defense and that TXNIP plays an important role as an inhibitor of NK cell-mediated macrophage activation by inhibiting the production of IFN-γ during bacterial infection.
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Affiliation(s)
- Dong Oh Kim
- Department of Innovative Toxicology Research, Korea Institute of Toxicology, Yuseong-gu, Daejeon 34114, Korea;
| | - Jae-Eun Byun
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 28644, Korea
| | - Won Sam Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Mi Jeong Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Korea;
| | - Jung Ha Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Hanna Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Eunji Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Tae-Don Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
| | - Suk Ran Yoon
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
| | - Ji-Yoon Noh
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Young-Jun Park
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (Y.-J.P.); (J.L.)
| | - Jungwoon Lee
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (Y.-J.P.); (J.L.)
| | - Hee Jun Cho
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Hee Gu Lee
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Biomolecular Science, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
| | - Sang-Hyun Min
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Chumbokro Dong-gu, Daegu 41061, Korea;
| | - Inpyo Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
- Correspondence: (I.C.); (H.J.)
| | - Haiyoung Jung
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
- Correspondence: (I.C.); (H.J.)
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Pujari R, Banerjee G. Impact of prebiotics on immune response: from the bench to the clinic. Immunol Cell Biol 2020; 99:255-273. [PMID: 32996638 DOI: 10.1111/imcb.12409] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 08/31/2020] [Accepted: 09/29/2020] [Indexed: 12/23/2022]
Abstract
Several preclinical and clinical studies have shown the immunomodulatory role exerted by prebiotics in regulating the immune response. In this review, we describe the mechanistic and clinical studies that decipher the cell signaling pathways implicated in the process. Prebiotic fibers are conventionally known to serve as substrate for probiotic commensal bacteria that release of short-chain fatty acids in the intestinal tract along with several other metabolites. Subsequently, they then act on the local as well as the systemic immune cells and the gut-associated epithelial cells, primarily through G-protein-coupled receptor-mediated pathways. However, other pathways including histone deacetylase inhibition and inflammasome pathway have also been implicated in regulating the immunomodulatory effect. The prebiotics can also induce a microbiota-independent effect by directly acting on the gut-associated epithelial and innate immune cells through the Toll-like receptors. The cumulative effect results in the maintenance of the epithelial barrier integrity and modulation of innate immunity through secretion of pro- and anti-inflammatory cytokines, switches in macrophage polarization and function, neutrophil recruitment and migration, dendritic cell and regulatory T-cell differentiation. Extending these in vitro and ex vivo observations, some prebiotics have been well investigated, with successful human and animal trials demonstrating the association between gut microbes and immunity biomarkers leading to improvement in health endpoints across populations. This review discusses scientific insights into the association between prebiotics, innate immunity and gut microbiome from in vitro to human oral intervention.
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Affiliation(s)
- Radha Pujari
- Innovation Centre, Tata Chemicals Ltd, Pune, Maharashtra, India
| | - Gautam Banerjee
- Innovation Centre, Tata Chemicals Ltd, Pune, Maharashtra, India
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32
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van der Heide SL, Xi Y, Upham JW. Natural Killer Cells and Host Defense Against Human Rhinoviruses Is Partially Dependent on Type I IFN Signaling. Front Cell Infect Microbiol 2020; 10:510619. [PMID: 33194777 PMCID: PMC7609819 DOI: 10.3389/fcimb.2020.510619] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 10/02/2020] [Indexed: 12/12/2022] Open
Abstract
Rhinovirus (RV), the causative agent of the common cold, causes only mild upper respiratory tract infections in healthy individuals, but can cause longer lasting and more severe pulmonary infections in people with chronic lung diseases and in the setting of immune suppression or immune deficiency. RV-infected lung structural cells release type I interferon (IFN-I), initiating the immune response, leading to protection against viruses in conjunction with migratory immune cells. However, IFN-I release is deficient in some people with asthma. Innate immune cells, such as natural killer (NK) cells, are proposed to play major roles in the control of viral infections, and may contribute to exacerbations of chronic lung diseases, such as asthma. In this study, we characterized the NK cell response to RV infection using an in vitro model of infection in healthy individuals, and determined the extent to which IFN-I signaling mediates this response. The results indicate that RV stimulation in vitro induces NK cell activation in healthy donors, leading to degranulation and the release of cytotoxic mediators and cytokines. IFN-I signaling was partly responsible for NK cell activation and functional responses to RV. Overall, our findings suggest the involvement of NK cells in the control of RV infection in healthy individuals. Further understanding of NK cell regulation may deepen our understanding of the mechanisms that contribute to susceptibility to RV infections in asthma and other chronic lung diseases.
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Affiliation(s)
- Saskia L van der Heide
- Lung and Allergy Research Centre, Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Yang Xi
- Lung and Allergy Research Centre, Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - John W Upham
- Lung and Allergy Research Centre, Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia.,Department of Respiratory Medicine, Princess Alexandra Hospital, Brisbane, QLD, Australia
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33
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Lymphocyte Immunosuppression and Dysfunction Contributing to Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS). Shock 2020; 55:723-741. [PMID: 33021569 DOI: 10.1097/shk.0000000000001675] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
ABSTRACT Persistent Inflammation, Immune Suppression, and Catabolism Syndrome (PICS) is a disease state affecting patients who have a prolonged recovery after the acute phase of a large inflammatory insult. Trauma and sepsis are two pathologies after which such an insult evolves. In this review, we will focus on the key clinical determinants of PICS: Immunosuppression and cellular dysfunction. Currently, relevant immunosuppressive functions have been attributed to both innate and adaptive immune cells. However, there are significant gaps in our knowledge, as for trauma and sepsis the immunosuppressive functions of these cells have mostly been described in acute phase of inflammation so far, and their clinical relevance for the development of prolonged immunosuppression is mostly unknown. It is suggested that the initial immune imbalance determines the development of PCIS. Additionally, it remains unclear what distinguishes the onset of immune dysfunction in trauma and sepsis and how this drives immunosuppression in these cells. In this review, we will discuss how regulatory T cells (Tregs), innate lymphoid cells, natural killer T cells (NKT cells), TCR-a CD4- CD8- double-negative T cells (DN T cells), and B cells can contribute to the development of post-traumatic and septic immunosuppression. Altogether, we seek to fill a gap in the understanding of the contribution of lymphocyte immunosuppression and dysfunction to the development of chronic immune disbalance. Further, we will provide an overview of promising diagnostic and therapeutic interventions, whose potential to overcome the detrimental immunosuppression after trauma and sepsis is currently being tested.
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34
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Rasid O, Chevalier C, Camarasa TMN, Fitting C, Cavaillon JM, Hamon MA. H3K4me1 Supports Memory-like NK Cells Induced by Systemic Inflammation. Cell Rep 2020; 29:3933-3945.e3. [PMID: 31851924 DOI: 10.1016/j.celrep.2019.11.043] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 09/06/2019] [Accepted: 11/08/2019] [Indexed: 12/24/2022] Open
Abstract
Natural killer (NK) cells are unique players in innate immunity and, as such, an attractive target for immunotherapy. NK cells display immune memory properties in certain models, but the long-term status of NK cells following systemic inflammation is unknown. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memory-like properties, showing increased production of IFNγ upon specific secondary stimulation. The NK cell memory response is detectable for at least 9 weeks and contributes to protection from E. coli infection upon adoptive transfer. Importantly, we reveal a mechanism essential for NK cell memory, whereby an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erases the enhancer and abolishes NK cell memory. Thus, NK cell memory develops after endotoxemia in a histone methylation-dependent manner, ensuring a heightened response to secondary stimulation.
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Affiliation(s)
- Orhan Rasid
- G5 Chromatine et Infection, Institut Pasteur, Paris, France; Unité Cytokines & Inflammation, Institut Pasteur, Paris, France.
| | | | - Tiphaine Marie-Noelle Camarasa
- G5 Chromatine et Infection, Institut Pasteur, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France
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35
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NK cells: energized yet exhausted in adult HLH. Blood 2020; 136:524-525. [PMID: 32730578 DOI: 10.1182/blood.2020006097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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36
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Karagiannis TT, Cleary JP, Gok B, Henderson AJ, Martin NG, Yajima M, Nelson EC, Cheng CS. Single cell transcriptomics reveals opioid usage evokes widespread suppression of antiviral gene program. Nat Commun 2020; 11:2611. [PMID: 32457298 PMCID: PMC7250875 DOI: 10.1038/s41467-020-16159-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 04/19/2020] [Indexed: 01/01/2023] Open
Abstract
Chronic opioid usage not only causes addiction behavior through the central nervous system, but also modulates the peripheral immune system. However, how opioid impacts the immune system is still barely characterized systematically. In order to understand the immune modulatory effect of opioids in an unbiased way, here we perform single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from opioid-dependent individuals and controls to show that chronic opioid usage evokes widespread suppression of antiviral gene program in naive monocytes, as well as in multiple immune cell types upon stimulation with the pathogen component lipopolysaccharide. Furthermore, scRNA-seq reveals the same phenomenon after a short in vitro morphine treatment. These findings indicate that both acute and chronic opioid exposure may be harmful to our immune system by suppressing the antiviral gene program. Our results suggest that further characterization of the immune modulatory effects of opioid is critical to ensure the safety of clinical opioids. Over 100 million of opioid prescriptions are issued yearly in the USA alone, but the impact of opioid use on the immune system is barely characterized. Here the authors report antiviral immune response is blunted in several types of blood cells from opioid-dependent individuals, and when healthy donor cells are exposed to morphine in a dish.
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Affiliation(s)
- Tanya T Karagiannis
- Program in Bioinformatics, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA.,Department of Biology, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA
| | - John P Cleary
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA.,Program in Molecular Biology, Cell Biology and Biochemistry, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA
| | - Busra Gok
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA.,Program in Cell and Molecular Biology, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA
| | - Andrew J Henderson
- Department of Medicine and Microbiology, Boston University School of Medicine, 650 Albany St, Boston, MA, 02215, USA
| | - Nicholas G Martin
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia
| | - Masanao Yajima
- Department of Mathematics and Statistics, Boston University, 111 Cummington Mall, Boston, MA, 02215, USA
| | - Elliot C Nelson
- Department of Psychiatry, Washington University School of Medicine, 660S. Euclid Ave, St. Louis, MO, 63110, USA
| | - Christine S Cheng
- Program in Bioinformatics, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA. .,Department of Biology, Boston University, 5 Cummington Mall, Boston, MA, 02215, USA. .,Program in Molecular Biology, Cell Biology and Biochemistry, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA. .,Program in Cell and Molecular Biology, Boston University, 24 Cummington Mall, Boston, MA, 02215, USA.
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Abstract
Sepsis, a life threating syndrome characterized by organ failure after infection, is the most common cause of death in hospitalized patients. The treatment of sepsis is generally supportive in nature, involving the administration of intravenous fluids, vasoactive substances and oxygen plus antibiotics to eliminate the pathogen. No drugs have been approved specifically for the treatment of sepsis, and clinical trials of potential therapies have failed to reduce mortality - suggesting that new approaches are needed. Abnormalities in the immune response elicited by the pathogen, ranging from excessive inflammation to immunosuppression, contribute to disease pathogenesis. Although hundreds of immunomodulatory agents are potentially available, it remains unclear which patient benefits from which immune therapy at a given time point. Results indicate the importance of personalized therapy, specifically the need to identify the type of intervention required by each individual patient at a given point in the disease process. To address this issue will require using biomarkers to stratify patients based on their individual immune status. This article reviews recent and ongoing clinical investigations using immunostimulatory or immunosuppressive therapies against sepsis including non-pharmacological and novel preclinical approaches.
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Toll-Like Receptors in Natural Killer Cells and Their Application for Immunotherapy. J Immunol Res 2020; 2020:2045860. [PMID: 32377528 PMCID: PMC7199539 DOI: 10.1155/2020/2045860] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 12/21/2019] [Indexed: 12/21/2022] Open
Abstract
Innate immunity represents the first barrier for host defense against microbial infection. Toll-like receptors (TLRs) are the most well-defined PRRs with respect to PAMP recognition and induction of innate immune responses. They recognize pathogen-associated molecular patterns (PAMPs) and trigger innate immune responses by inducing inflammatory cytokines, chemokines, antigen-presenting molecules, and costimulatory molecules. TLRs are expressed either on the cell surface or within endosomes of innate immune cells. NK cells are one of the innate immune cells and also express TLRs to recognize or respond to PAMPs. TLRs in NK cells induce the innate immune responses against bacterial and viral infections via inducing NK cytotoxicity and cytokine production. In this review, we will discuss the expression and cellular function of TLRs in NK cells and also introduce some therapeutic applications of TLR agonists for NK cell-mediated immunotherapy.
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S100A14 Is Increased in Activated NK Cells and Plasma of HIV-Exposed Seronegative People Who Inject Drugs and Promotes Monocyte-NK Crosstalk. J Acquir Immune Defic Syndr 2019; 80:234-241. [PMID: 30422902 DOI: 10.1097/qai.0000000000001911] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND HIV-exposed seronegative people who inject drugs (HESN-PWID) have been shown to have increased natural killer (NK) cell and myeloid activation when compared with control donors. METHODS We investigated potential mechanisms maintaining NK activation by conducting quantitative proteome comparisons of NK cells from HESN-PWID subjects and control donors. Proteins upregulated in NK cells were measured in the plasma of HESN-PWID subjects by ELISA and further investigated for their ability to induce innate immune activation in vitro. RESULTS The NK cell proteome comparison showed markedly higher levels of interferon-stimulated proteins and S100 proteins, including S100A14. Consistent with these results, we observed significantly higher levels of S100A14 in the plasma of HESN-PWID subjects compared with controls (P = 0.033, n = 25). In vitro, the addition of recombinant S100A14 protein significantly activated NK cells in a peripheral blood mononuclear cell mixture (P = 0.011, n = 9), but not purified NK cells alone. Treatment of purified monocytes with recombinant S100A14 protein induced secretion of TNF-alpha and led to significantly higher NK CD69 activation (P = 0.0156, n = 7) in a co-culture through a TLR4-dependent interaction. CONCLUSIONS Our study identified S100A14 as a novel protein increased within NK cells and plasma of HESN-PWID subjects with the capacity to sustain NK activation through TLR4-dependent activation of myeloid cells.
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Cao C, Yu M, Chai Y. Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis. Cell Death Dis 2019; 10:782. [PMID: 31611560 PMCID: PMC6791888 DOI: 10.1038/s41419-019-2015-1] [Citation(s) in RCA: 206] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 08/28/2019] [Accepted: 09/02/2019] [Indexed: 02/07/2023]
Abstract
Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection that leads to uncontrolled inflammatory response followed by immunosuppression. However, despite the high mortality rate, no specific treatment modality or drugs with high efficacy is available for sepsis to date. Although improved treatment strategies have increased the survival rate during the initial state of excessive inflammatory response, recent trends in sepsis show that mortality occurs at a period of continuous immunosuppressive state in which patients succumb to secondary infections within a few weeks or months due to post-sepsis “immune paralysis.” Immune cell alteration induced by uncontrolled apoptosis has been considered a major cause of significant immunosuppression. Particularly, apoptosis of lymphocytes, including innate immune cells and adaptive immune cells, is associated with a higher risk of secondary infections and poor outcomes. Multiple postmortem studies have confirmed that sepsis-induced immune cell apoptosis occurs in all age groups, including neonates, pediatric, and adult patients, and it is considered to be a primary contributing factor to the immunosuppressive pathophysiology of sepsis. Therapeutic perspectives targeting apoptosis through various strategies could improve survival in sepsis. In this review article, we will focus on describing the major apoptosis process of immune cells with respect to physiologic and molecular mechanisms. Further, advances in apoptosis-targeted treatment modalities for sepsis will also be discussed.
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Affiliation(s)
- Chao Cao
- Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Medical University, Tianjin, China.,Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Muming Yu
- Tianjin Medical University General Hospital, Tianjin, China
| | - Yanfen Chai
- Tianjin Medical University General Hospital, Tianjin, China. .,Tianjin Medical University, Tianjin, China.
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Cavaillon JM, Giamarellos-Bourboulis EJ. Immunosuppression is Inappropriately Qualifying the Immune Status of Septic and SIRS Patients. Shock 2019; 52:307-317. [PMID: 30239420 DOI: 10.1097/shk.0000000000001266] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Immunosuppression is the most commonly used concept to qualify the immune status of patients with either sterile systemic inflammatory response syndrome (SIRS) or sepsis. In this review we attempt to demonstrate that the concept of immunosuppression is an oversimplification of the complex anti-inflammatory response that occurs in patients dealing with a severe sterile or infectious insult. Particularly, the immune status of leukocytes varies greatly depending on the compartment from where they are derived from. Furthermore, although certain functions of immune cells present in the blood stream or in the hematopoietic organs can be significantly diminished, other functions are either unchanged or even enhanced. This juxtaposition illustrates that there is no global defect. The mechanisms called reprogramming or trained innate immunity are probably aimed at preventing a generalized deleterious inflammatory reaction, and work to maintain the defense mechanisms at their due levels.
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Kumar V. Natural killer cells in sepsis: Underprivileged innate immune cells. Eur J Cell Biol 2019; 98:81-93. [DOI: 10.1016/j.ejcb.2018.12.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/15/2018] [Accepted: 12/17/2018] [Indexed: 02/06/2023] Open
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The Role of O-Antigen in LPS-Induced Activation of Human NK Cells. J Immunol Res 2019; 2019:3062754. [PMID: 31236419 PMCID: PMC6545784 DOI: 10.1155/2019/3062754] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/07/2019] [Accepted: 03/03/2019] [Indexed: 11/19/2022] Open
Abstract
NK cells can be stimulated by bacterial lipopolysaccharides (LPS). Unlike macrophages, human NK cells do not express or express very low level of surface TLR4 receptor normally required for the LPS stimulation. This has led to the assumption that the mechanisms of stimulating action of LPS on macrophages and NK cells differs. In this work, we investigated the effects of different forms of E. coli LPS, including mutants lacking O-antigen structures, and deacylated LPS on IFNγ production by purified human NK cells. The main findings were the following: (1) NK cells were more sensitive to the S-forms of LPS than the R-forms (LPS lacking O-antigen); (2) LPS triggered a significant increase in IFNγ production by NK cells in concentrations about 1000 times higher than those that can induce cytokine production by macrophages; (3) the composition and structure of saccharide part of LPS have a strong influence on its observed effects on NK cells; and (4) LPS fully retained the ability to trigger cytokine production in NK cells in serum-free media. The acquired data demonstrated that the presence and structure of O-antigen affects the LPS-induced activation of human NK cells.
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Poggi A, Benelli R, Venè R, Costa D, Ferrari N, Tosetti F, Zocchi MR. Human Gut-Associated Natural Killer Cells in Health and Disease. Front Immunol 2019; 10:961. [PMID: 31130953 PMCID: PMC6509241 DOI: 10.3389/fimmu.2019.00961] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 04/15/2019] [Indexed: 12/14/2022] Open
Abstract
It is well established that natural killer (NK) cells are involved in both innate and adaptive immunity. Indeed, they can recognize molecules induced at the cell surface by stress signals and virus infections. The functions of NK cells in the gut are much more complex. Gut NK cells are not precisely organized in lymphoid aggregates but rather scattered in the epithelium or in the stroma, where they come in contact with a multitude of antigens derived from commensal or pathogenic microorganisms in addition to components of microbiota. Furthermore, NK cells in the bowel interact with several cell types, including epithelial cells, fibroblasts, macrophages, dendritic cells, and T lymphocytes, and contribute to the maintenance of immune homeostasis and development of efficient immune responses. NK cells have a key role in the response to intestinal bacterial infections, primarily through production of IFNγ, which can stimulate recruitment of additional NK cells from peripheral blood leading to amplification of the anti-bacterial immune response. Additionally, NK cells can have a role in the pathogenesis of gut autoimmune inflammatory bowel diseases (IBDs), such as Crohn's Disease and Ulcerative Colitis. These diseases are considered relevant to the generation of gastrointestinal malignancies. Indeed, the role of gut-associated NK cells in the immune response to bowel cancers is known. Thus, in the gut immune system, NK cells play a dual role, participating in both physiological and pathogenic processes. In this review, we will analyze the known functions of NK cells in the gut mucosa both in health and disease, focusing on the cross-talk among bowel microenvironment, epithelial barrier integrity, microbiota, and NK cells.
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Affiliation(s)
- Alessandro Poggi
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Roberto Benelli
- Immunology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Roberta Venè
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Delfina Costa
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Nicoletta Ferrari
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Francesca Tosetti
- Molecular Oncology and Angiogenesis Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Maria Raffaella Zocchi
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Patra MC, Shah M, Choi S. Toll-like receptor-induced cytokines as immunotherapeutic targets in cancers and autoimmune diseases. Semin Cancer Biol 2019; 64:61-82. [PMID: 31054927 DOI: 10.1016/j.semcancer.2019.05.002] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 04/27/2019] [Accepted: 05/01/2019] [Indexed: 12/14/2022]
Abstract
Immune cells of the myeloid and lymphoid lineages express Toll-like receptors (TLRs) to recognize pathogenic components or cellular debris and activate the immune system through the secretion of cytokines. Cytokines are signaling molecules that are structurally and functionally distinct from one another, although their secretion profiles and signaling cascades often overlap. This situation gives rise to pleiotropic cell-to-cell communication pathways essential for protection from infections as well as cancers. Nonetheless, deregulated signaling can have detrimental effects on the host, in the form of inflammatory or autoimmune diseases. Because cytokines are associated with numerous autoimmune and cancerous conditions, therapeutic strategies to modulate these molecules or their biological responses have been immensely beneficial over the years. There are still challenges in the regulation of cytokine function in patients, even in those who take approved biological therapeutics. In this review, our purpose is to discuss the differential expression patterns of TLR-regulated cytokines and their cell type specificity that is associated with cancers and immune-system-related diseases. In addition, we highlight key structural features and molecular recognition of cytokines by receptors; these data have facilitated the development and approval of several biologics for the treatment of autoimmune diseases and cancers.
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Affiliation(s)
- Mahesh Chandra Patra
- Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea
| | - Masaud Shah
- Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, 16499, Republic of Korea.
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Kleinertz H, Hepner-Schefczyk M, Ehnert S, Claus M, Halbgebauer R, Boller L, Huber-Lang M, Cinelli P, Kirschning C, Flohé S, Sander A, Waydhas C, Vonderhagen S, Jäger M, Dudda M, Watzl C, Flohé SB. Circulating growth/differentiation factor 15 is associated with human CD56 bright natural killer cell dysfunction and nosocomial infection in severe systemic inflammation. EBioMedicine 2019; 43:380-391. [PMID: 30992245 PMCID: PMC6557805 DOI: 10.1016/j.ebiom.2019.04.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 03/18/2019] [Accepted: 04/08/2019] [Indexed: 12/12/2022] Open
Abstract
Background Systemic inflammation induced by sterile or infectious insults is associated with an enhanced susceptibility to life-threatening opportunistic, mostly bacterial, infections due to unknown pathogenesis. Natural killer (NK) cells contribute to the defence against bacterial infections through the release of Interferon (IFN) γ in response to Interleukin (IL) 12. Considering the relevance of NK cells in the immune defence we investigated whether the function of NK cells is disturbed in patients suffering from serious systemic inflammation. Methods NK cells from severely injured patients were analysed from the first day after the initial inflammatory insult until the day of discharge in terms of IL-12 receptor signalling and IFN-γ synthesis. Findings During systemic inflammation, the expression of the IL-12 receptor β2 chain, phosphorylation of signal transducer and activation 4, and IFN-γ production on/in NK cells was impaired upon exposure to Staphylococcus aureus. The profound suppression of NK cells developed within 24 h after the initial insult and persisted for several weeks. NK cells displayed signs of exhaustion. Extrinsic changes were mediated by the early and long-lasting presence of growth/differentiation factor (GDF) 15 in the circulation that signalled through the transforming growth factor β receptor I and activated Smad1/5. Moreover, the concentration of GDF-15 in the serum inversely correlated with the IL-12 receptor β2 expression on NK cells and was enhanced in patients who later acquired septic complications. Interpretation GDF-15 is associated with the development of NK cell dysfunction during systemic inflammation and might represent a novel target to prevent nosocomial infections. Fund The study was supported by the Department of Orthopaedics and Trauma Surgery, University Hospital Essen.
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Affiliation(s)
- Holger Kleinertz
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Monika Hepner-Schefczyk
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Sabrina Ehnert
- Siegfried Weller Institute for Trauma Research, University of Tübingen, Tübingen, Germany
| | - Maren Claus
- Leibniz Research Centre for Working Environment and Human Factors, IfADo, TU-Dortmund, Dortmund, Germany
| | - Rebecca Halbgebauer
- Institute of Clinical and Experimental Trauma-Immunology, University of Ulm, Ulm, Germany
| | - Lea Boller
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology, University of Ulm, Ulm, Germany
| | - Paolo Cinelli
- Division of Trauma Surgery, Department of Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Carsten Kirschning
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Sascha Flohé
- Department of Hand- and Trauma Surgery, University Hospital Dusseldorf, University Dusseldorf, Dusseldorf, Germany
| | - André Sander
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Christian Waydhas
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Sonja Vonderhagen
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Marcus Jäger
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Marcel Dudda
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Carsten Watzl
- Leibniz Research Centre for Working Environment and Human Factors, IfADo, TU-Dortmund, Dortmund, Germany
| | - Stefanie B Flohé
- Department of Orthopedics and Trauma Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
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Bruse N, Leijte GP, Pickkers P, Kox M. New frontiers in precision medicine for sepsis-induced immunoparalysis. Expert Rev Clin Immunol 2019; 15:251-263. [PMID: 30572728 DOI: 10.1080/1744666x.2019.1562336] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION In the last decade, the sepsis research field has shifted focus from targeting hyperinflammation to reversing sepsis-induced immunoparalysis. Sepsis-induced immunoparalysis is very heterogeneous: the magnitude and the nature of the underlying immune defects differ considerably between patients, but also within individuals over time. Therefore, a 'one-treatment-fits-all' strategy for sepsis-induced immunoparalysis is bound to fail, and an individualized 'precision medicine' approach is required. Such a strategy is nevertheless hampered by the unsuitability of the currently available markers to identify the many immune defects that can manifest in individual patients. Areas covered: We describe the currently available markers for sepsis-induced immunoparalysis and limitations pertaining to their use. Furthermore, future prospects and caveats are discussed, focusing on 'omics' approaches: genomics, transcriptomics, epigenomics, and metabolomics. Finally, we present a contemporary overview of adjuvant immunostimulatory therapies. Expert opinion: The integration of multiple omics techniques offers a systems biology approach which can yield biomarker profiles that accurately and comprehensively gauge the extent and nature of sepsis-induced immunoparalysis. We expect this development to be instrumental in facilitating precision medicine for sepsis-induced immunoparalysis, consisting of the application of targeted immunostimulatory therapies and follow-up measurements to monitor the response to treatment and to titrate or adjust medication.
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Affiliation(s)
- Niklas Bruse
- a Department of Intensive Care Medicine , Radboud University Medical Center , Nijmegen , The Netherlands.,b Radboud Center for Infectious Diseases , Radboud University Medical Center , Nijmegen , The Netherlands
| | - Guus P Leijte
- a Department of Intensive Care Medicine , Radboud University Medical Center , Nijmegen , The Netherlands.,b Radboud Center for Infectious Diseases , Radboud University Medical Center , Nijmegen , The Netherlands
| | - Peter Pickkers
- a Department of Intensive Care Medicine , Radboud University Medical Center , Nijmegen , The Netherlands.,b Radboud Center for Infectious Diseases , Radboud University Medical Center , Nijmegen , The Netherlands
| | - Matthijs Kox
- a Department of Intensive Care Medicine , Radboud University Medical Center , Nijmegen , The Netherlands.,b Radboud Center for Infectious Diseases , Radboud University Medical Center , Nijmegen , The Netherlands
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Pathophysiology of Acute Illness and Injury. OPERATIVE TECHNIQUES AND RECENT ADVANCES IN ACUTE CARE AND EMERGENCY SURGERY 2019. [PMCID: PMC7122041 DOI: 10.1007/978-3-319-95114-0_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The pathophysiology of acute illness and injury recognizes three main effectors: infection, trauma, and ischemia-reperfusion injury. Each of them can act by itself or in combination with the other two in developing a systemic inflammatory reaction syndrome (SIRS) that is a generalized reaction to the morbid event. The time course of SIRS is variable and influenced by the number and severity of subsequent insults (e.g., reparative surgery, acquired hospital infections). It occurs simultaneously with a complex of counter-regulatory mechanisms (compensatory anti-inflammatory response syndrome, CARS) that limit the aggressive effects of SIRS. In adjunct, a progressive dysfunction of the acquired (lymphocytes) immune system develops with increased risk for immunoparalysis and associated infectious complications. Both humoral and cellular effectors participate to the development of SIRS and CARS. The most important humoral mediators are pro-inflammatory (IL-1β, IL-6, IL-8, IL-12) and anti-inflammatory (IL-4, IL-10) cytokines and chemokines, complement, leukotrienes, and PAF. Effector cells include neutrophils, monocytes, macrophages, lymphocytes, and endothelial cells. The endothelium is a key factor for production of remote organ damage as it exerts potent chemo-attracting effects on inflammatory cells, allows for leukocyte trafficking into tissues and organs, and promotes further inflammation by cytokines release. Moreover, the loss of vasoregulatory properties and the increased permeability contribute to the development of hypotension and tissue edema. Finally, the disseminated activation of the coagulation cascade causes the widespread deposition of microthrombi with resulting maldistribution of capillary blood flow and ultimately hypoxic cellular damage. This mechanism together with increased vascular permeability and vasodilation is responsible for the development of the multiple organ dysfunction syndrome (MODS).
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Mahmoodpoor A, Paknezhad S, Shadvar K, Hamishehkar H, Movassaghpour AA, Sanaie S, Ghamari AA, Soleimanpour H. Flow Cytometry of CD64, HLA-DR, CD25, and TLRs for Diagnosis and Prognosis of Sepsis in Critically Ill Patients Admitted to the Intensive Care Unit: A Review Article. Anesth Pain Med 2018; 8:e83128. [PMID: 30719416 PMCID: PMC6347736 DOI: 10.5812/aapm.83128] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 10/24/2018] [Accepted: 11/15/2018] [Indexed: 01/15/2023] Open
Abstract
Sepsis is an important health problem with a high burden on health systems. Finding new aspects of immune system function in sepsis showed a new role for flow cytometry in the diagnosis of sepsis. We made a review on the role of CD64, HLA-DR, CD25, and TLRs as more useful flow cytometric tools in diagnosing sepsis, both in adults, and neonates. According to our results, we concluded that for diagnosis and treatment of the septic, flow cytometry can play an important role so that it can be used as a novel method in individualized treatment of septic patients based on their immune system situation.
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Affiliation(s)
- Ata Mahmoodpoor
- Anesthesiology Research Team, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyedpouya Paknezhad
- Emergency Medicine Research Team, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kamran Shadvar
- Anesthesiology Research Team, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Hamishehkar
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Movassaghpour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sarvin Sanaie
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Ghamari
- Anesthesiology Research Team, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Soleimanpour
- Emergency Medicine Research Team, Tabriz University of Medical Sciences, Tabriz, Iran
- Corresponding Author: Emergency Medicine Research Team, Tabriz University of Medical Sciences, Tabriz, Iran. Tel: +98-9141164134, Fax: +98-4133341994,
E-mail:
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Kaszubowska L, Foerster J, Schetz D, Kmieć Z. CD56bright cells respond to stimulation until very advanced age revealing increased expression of cellular protective proteins SIRT1, HSP70 and SOD2. Immun Ageing 2018; 15:31. [PMID: 30534181 PMCID: PMC6262966 DOI: 10.1186/s12979-018-0136-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 11/02/2018] [Indexed: 01/15/2023]
Abstract
BACKGROUND NK cells are cytotoxic lymphocytes of innate immunity composed of: cytotoxic CD56dim and immunoregulatory CD56bright cells. The study aimed to analyze the expression of cellular protective proteins: sirtuin 1 (SIRT1), heat shock protein 70 (HSP70) and manganese superoxide dismutase (SOD2) in CD56dim and CD56bright NK cells of the young, seniors aged under 85 ('the old') and seniors aged over 85 ('the oldest'). We studied both non-stimulated NK cells and cells stimulated by IL-2, LPS or PMA with ionomycin. The expression level of proinflammatory cytokines TNF and IFN-γ was also assessed in NK cell subsets and some relationships between the studied parameters were analyzed. RESULTS CD56bright cells showed sensitivity to most of the applied stimulatory agents until very advanced age in regards to the expression of SIRT1 and intracellular HSP70. On the contrary, CD56dim cells, sensitive to stimulation by most of the stimulatory agents in the young and the old, in the oldest lost this sensitivity and presented rather high, constant expression of SIRT1 and HSP70, resistant to further stimulation. With reference to SOD2 expression, CD56dim cells were insensitive to stimulation in the young, but their sensitivity increased with ageing. CD56bright cells were sensitive to most of the applied agents in the young and the old but in the oldest they responded to all of the stimulatory agents used in the study. Similarly, both NK cell subsets were sensitive to stimulation until very advanced age in regards to the expression of TNF and IFN-γ. CONCLUSIONS CD56bright cells maintained sensitivity to stimulation until very advanced age presenting also an increased expression of SIRT1 and HSP70. CD56dim cells showed a constantly increased expression of these cellular protective proteins in the oldest, insensitive for further stimulation. The oldest, however, did not reveal an increased level of SOD2 expression, but it was significantly elevated in both NK cell subsets after stimulation.The pattern of expression of the studied cellular protective proteins in ageing process revealed the adaptation of NK cells to stress response in the oldest seniors which might accompany the immunosenescence and contribute to the long lifespan of this group of the elderly.
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Affiliation(s)
- Lucyna Kaszubowska
- Department of Histology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Jerzy Foerster
- Department of Social and Clinical Gerontology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
| | - Daria Schetz
- Department of Pharmacology, Medical University of Gdańsk, Dębowa 23, 80-204 Gdańsk, Poland
| | - Zbigniew Kmieć
- Department of Histology, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland
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