|
1
|
Cavaillon JM, Chaudry IH. Facing stress and inflammation: From the cell to the planet. World J Exp Med 2024; 14:96422. [PMID: 39713080 PMCID: PMC11551703 DOI: 10.5493/wjem.v14.i4.96422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/27/2024] [Accepted: 09/19/2024] [Indexed: 10/31/2024] Open
Abstract
As identified in 1936 by Hans Selye, stress is shaping diseases through the induction of inflammation. But inflammation display some yin yang properties. On one hand inflammation is merging with the innate immune response aimed to fight infectious or sterile insults, on the other hand inflammation favors chronic physical or psychological disorders. Nature has equipped the cells, the organs, and the individuals with mediators and mechanisms that allow them to deal with stress, and even a good stress (eustress) has been associated with homeostasis. Likewise, societies and the planet are exposed to stressful settings, but wars and global warming suggest that the regulatory mechanisms are poorly efficient. In this review we list some inducers of the physiological stress, psychologic stress, societal stress, and planetary stress, and mention some of the great number of parameters which affect and modulate the response to stress and render it different from an individual to another, from the cellular level to the societal one. The cell, the organ, the individual, the society, and the planet share many stressors of which the consequences are extremely interconnected ending in the domino effect and the butterfly effect.
Collapse
Affiliation(s)
| | - Irshad H Chaudry
- Department of Surgery, University of Alabama Birmingham, Birmingham, AL 35294, United States
| |
Collapse
|
|
2
|
Llitjos JF, Carrol ED, Osuchowski MF, Bonneville M, Scicluna BP, Payen D, Randolph AG, Witte S, Rodriguez-Manzano J, François B. Enhancing sepsis biomarker development: key considerations from public and private perspectives. Crit Care 2024; 28:238. [PMID: 39003476 PMCID: PMC11246589 DOI: 10.1186/s13054-024-05032-9] [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: 05/03/2024] [Accepted: 07/10/2024] [Indexed: 07/15/2024] Open
Abstract
Implementation of biomarkers in sepsis and septic shock in emergency situations, remains highly challenging. This viewpoint arose from a public-private 3-day workshop aiming to facilitate the transition of sepsis biomarkers into clinical practice. The authors consist of international academic researchers and clinician-scientists and industry experts who gathered (i) to identify current obstacles impeding biomarker research in sepsis, (ii) to outline the important milestones of the critical path of biomarker development and (iii) to discuss novel avenues in biomarker discovery and implementation. To define more appropriately the potential place of biomarkers in sepsis, a better understanding of sepsis pathophysiology is mandatory, in particular the sepsis patient's trajectory from the early inflammatory onset to the late persisting immunosuppression phase. This time-varying host response urges to develop time-resolved test to characterize persistence of immunological dysfunctions. Furthermore, age-related difference has to be considered between adult and paediatric septic patients. In this context, numerous barriers to biomarker adoption in practice, such as lack of consensus about diagnostic performances, the absence of strict recommendations for sepsis biomarker development, cost and resources implications, methodological validation challenges or limited awareness and education have been identified. Biomarker-guided interventions for sepsis to identify patients that would benefit more from therapy, such as sTREM-1-guided Nangibotide treatment or Adrenomedullin-guided Enibarcimab treatment, appear promising but require further evaluation. Artificial intelligence also has great potential in the sepsis biomarker discovery field through capability to analyse high volume complex data and identify complex multiparametric patient endotypes or trajectories. To conclude, biomarker development in sepsis requires (i) a comprehensive and multidisciplinary approach employing the most advanced analytical tools, (ii) the creation of a platform that collaboratively merges scientific and commercial needs and (iii) the support of an expedited regulatory approval process.
Collapse
Affiliation(s)
- Jean-Francois Llitjos
- Open Innovation and Partnerships (OI&P), bioMérieux S.A., Marcy l'Etoile, France.
- Anesthesiology and Critical Care Medicine, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France.
| | - Enitan D Carrol
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool Institute of Infection Veterinary and Ecological Sciences, Liverpool, UK
- Department of Paediatric Infectious Diseases and Immunology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
| | - Marcin F Osuchowski
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Vienna, Austria
| | - Marc Bonneville
- Medical and Scientific Affairs, Institut Mérieux, Lyon, France
| | - 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
| | - Didier Payen
- Paris 7 University Denis Diderot, Paris Sorbonne, Cité, France
| | - Adrienne G Randolph
- Departments of Anaesthesia and Pediatrics, Harvard Medical School, Boston, MA, USA
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
| | | | | | - Bruno François
- Medical-Surgical Intensive Care Unit, Réanimation Polyvalente, Dupuytren University Hospital, CHU de Limoges, 2 Avenue Martin Luther King, 87042, Limoges Cedex, France.
- Inserm CIC 1435, Dupuytren University Hospital, Limoges, France.
- Inserm UMR 1092, Medicine Faculty, University of Limoges, Limoges, France.
| |
Collapse
|
|
3
|
Pei H, Qu J, Chen J, Zhao G, Lu Z. S100A9 as a Key Myocardial Injury Factor Interacting with ATP5 Exacerbates Mitochondrial Dysfunction and Oxidative Stress in Sepsis-Induced Cardiomyopathy. J Inflamm Res 2024; 17:4483-4503. [PMID: 39006491 PMCID: PMC11246037 DOI: 10.2147/jir.s457340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 06/22/2024] [Indexed: 07/16/2024] Open
Abstract
Purpose Sepsis-induced cardiomyopathy (SICM) is a prevalent cardiac dysfunction caused by sepsis. Mitochondrial dysfunction is a crucial pathogenic factor associated with adverse cardiovascular adverse events; however, research on SICM remains insufficient. Methods To investigate the factors contributing to the pathological progression of SICM, we performed a comprehensive analysis of transcriptomic data from the GEO database using bioinformatics and machine learning techniques. CRISPR-Cas9 S100A9 knockout mice and primary cardiomyocytes were exposed to lipopolysaccharide to simulate SICM. Transcriptome analysis and mass spectrometry of primary cardiomyocytes were used to determine the potential pathogenic mechanisms of S100A9. The mitochondrial ultrastructure and mitochondrial membrane potential (MMP) were detected using transmission electron microscopy and flow cytometry, respectively. Pink1/Parkin and Drp1 proteins were detected using Western blotting to evaluate mitochondrial autophagy and division. The mtDNA and mRNA levels of mitochondrial transcription factors and synthases were evaluated using real-time polymerase chain reaction. Results Bioinformatics analysis identified 12 common differentially expressed genes, including SERPINA3N, LCN2, MS4A6D, LRG1, OSMR, SOCS3, FCGR2b, S100A9, S100A8, CASP4, ABCA8A, and NFKBIZ. Significant S100A9 upregulation was closely associated with myocardial injury exacerbation and cardiac function deterioration. GSEA revealed that myocardial contractile function, oxidative stress, and mitochondrial function were significantly affected by S100A9. Knocking out S100A9 alleviates the inflammatory response and mitochondrial dysfunction. The interaction of S100A9 with ATP5 enhanced mitochondrial division and autophagy, inhibited MMP and ATP synthesis, and induced oxidative stress, which are related to the Nlrp3-Nfkb-Caspase1 and Drp1-Pink1-Parkin signaling pathways. The expression of mitochondrial transcription factors (TFAM and TFBM) and ATP synthetases (ATP6 and ATP8, as well as COX1, COX2, and COX3) was further suppressed by S100A9 in SICM. Targeted S100A9 inhibition by paquinimod partially reversed myocardial mitochondrial dysfunction and oxidative stress. Conclusion The interaction of S100A9 with ATP5 exacerbates myocardial damage in sepsis by inducing mitochondrial dysfunction and oxidative stress.
Collapse
Affiliation(s)
- Hui Pei
- Emergency Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Jie Qu
- Emergency Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Jianming Chen
- Emergency Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Guangju Zhao
- Emergency Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - ZhongQiu Lu
- Emergency Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
- Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou, People’s Republic of China
| |
Collapse
|
|
4
|
Cavaillon JM, Chousterman BG, Skirecki T. Compartmentalization of the inflammatory response during bacterial sepsis and severe COVID-19. JOURNAL OF INTENSIVE MEDICINE 2024; 4:326-340. [PMID: 39035623 PMCID: PMC11258514 DOI: 10.1016/j.jointm.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 01/04/2024] [Accepted: 01/06/2024] [Indexed: 07/23/2024]
Abstract
Acute infections cause local and systemic disorders which can lead in the most severe forms to multi-organ failure and eventually to death. The host response to infection encompasses a large spectrum of reactions with a concomitant activation of the so-called inflammatory response aimed at fighting the infectious agent and removing damaged tissues or cells, and the anti-inflammatory response aimed at controlling inflammation and initiating the healing process. Fine-tuning at the local and systemic levels is key to preventing local and remote injury due to immune system activation. Thus, during bacterial sepsis and Coronavirus disease 2019 (COVID-19), concomitant systemic and compartmentalized pro-inflammatory and compensatory anti-inflammatory responses are occurring. Immune cells (e.g., macrophages, neutrophils, natural killer cells, and T-lymphocytes), as well as endothelial cells, differ from one compartment to another and contribute to specific organ responses to sterile and microbial insult. Furthermore, tissue-specific microbiota influences the local and systemic response. A better understanding of the tissue-specific immune status, the organ immunity crosstalk, and the role of specific mediators during sepsis and COVID-19 can foster the development of more accurate biomarkers for better diagnosis and prognosis and help to define appropriate host-targeted treatments and vaccines in the context of precision medicine.
Collapse
Affiliation(s)
| | - Benjamin G. Chousterman
- Department of Anesthesia and Critical Care, Lariboisière University Hospital, DMU Parabol, APHP Nord, Paris, France
- Inserm U942, University of Paris, Paris, France
| | - Tomasz Skirecki
- Department of Translational Immunology and Experimental Intensive Care, Centre of Postgraduate Medical Education, Warsaw, Poland
| |
Collapse
|
|
5
|
Li Y, Nie Y, Yang X, Liu Y, Deng X, Hayashi Y, Plummer R, Li Q, Luo N, Kasai T, Okumura T, Kamishibahara Y, Komoto T, Ohkuma T, Okamoto S, Isobe Y, Yamaguchi K, Furukawa Y, Taniguchi H. Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis. Cell Rep 2024; 43:113918. [PMID: 38451817 DOI: 10.1016/j.celrep.2024.113918] [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: 08/10/2023] [Revised: 12/29/2023] [Accepted: 02/19/2024] [Indexed: 03/09/2024] Open
Abstract
Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant organoid dysfunction that closely resembles the pathological characteristics of the human septic liver. Furthermore, we observe a notable functional recovery in KuLOs upon endotoxin elimination, which is accelerated by using Toll-like receptor-4-directed endotoxin antagonist. Our study represents a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies.
Collapse
Affiliation(s)
- Yang Li
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Yunzhong Nie
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
| | - Xia Yang
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Yang Liu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xiaoshan Deng
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Yoshihito Hayashi
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Riana Plummer
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Qinglin Li
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Na Luo
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Department of Pathology, Immunology and Microbiology, Graduate School of Medicine, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Toshiharu Kasai
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Takashi Okumura
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Yu Kamishibahara
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Takemasa Komoto
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Takuya Ohkuma
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Satoshi Okamoto
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Yumiko Isobe
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Kiyoshi Yamaguchi
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Yoichi Furukawa
- Division of Clinical Genome Research, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan
| | - Hideki Taniguchi
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan; Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
| |
Collapse
|
|
6
|
Brusletto BS, Hellerud BC, Øvstebø R, Brandtzaeg P. Neisseria meningitidis accumulate in large organs during meningococcal sepsis. Front Cell Infect Microbiol 2023; 13:1298360. [PMID: 38089821 PMCID: PMC10713808 DOI: 10.3389/fcimb.2023.1298360] [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: 09/21/2023] [Accepted: 11/07/2023] [Indexed: 12/18/2023] Open
Abstract
Background Neisseria meningitidis (Nm) is the cause of epidemic meningitis and fulminant meningococcal septicemia. The clinical presentations and outcome of meningococcal septic shock is closely related to the circulating levels of lipopolysaccharides (LPS) and of Neisseria meningitidis DNA (Nm DNA). We have previously explored the distribution of Nm DNA in tissues from large organs of patients dying of meningococcal septic shock and in a porcine meningococcal septic shock model. Objective 1) To explore the feasibility of measuring LPS levels in tissues from the large organs in patients with meningococcal septic shock and in a porcine meningococcal septic shock model. 2) To evaluate the extent of contamination of non-specific LPS during the preparation of tissue samples. Patients and methods Plasma, serum, and fresh frozen (FF) tissue samples from the large organs of three patients with lethal meningococcal septic shock and two patients with lethal pneumococcal disease. Samples from a porcine meningococcal septic shock model were included. Frozen tissue samples were thawed, homogenized, and prepared for quantification of LPS by Pyrochrome® Limulus Amoebocyte Lysate (LAL) assay. Results N. meningitidis DNA and LPS was detected in FF tissue samples from large organs in all patients with meningococcal septic shock. The lungs are the organs with the highest LPS and Nm DNA concentration followed by the heart in two of the three meningococcal shock patients. Nm DNA was not detected in any plasma or tissue sample from patients with lethal pneumococcal infection. LPS was detected at a low level in all FF tissues from the two patients with lethal pneumococcal disease. The experimental porcine meningococcal septic shock model indicates that also in porcinis the highest LPS and Nm DNA concentration are detected in lungs tissue samples. The quantification analysis showed that the highest concentration of both Nm DNA and LPS are in the organs and not in the circulation of patients with lethal meningococcal septic shock. This was also shown in the experimental porcine meningococcal septic shock model. Conclusion Our results suggest that LPS can be quantified in mammalian tissues by using the LAL assay.
Collapse
Affiliation(s)
| | | | - Reidun Øvstebø
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Petter Brandtzaeg
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
- Department of Pediatrics, Oslo University Hospital, Nydalen, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| |
Collapse
|
|
7
|
Cleuren A, Molema G. Organotypic heterogeneity in microvascular endothelial cell responses in sepsis-a molecular treasure trove and pharmacological Gordian knot. Front Med (Lausanne) 2023; 10:1252021. [PMID: 38020105 PMCID: PMC10665520 DOI: 10.3389/fmed.2023.1252021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
In the last decades, it has become evident that endothelial cells (ECs) in the microvasculature play an important role in the pathophysiology of sepsis-associated multiple organ dysfunction syndrome (MODS). Studies on how ECs orchestrate leukocyte recruitment, control microvascular integrity and permeability, and regulate the haemostatic balance have provided a wealth of knowledge and potential molecular targets that could be considered for pharmacological intervention in sepsis. Yet, this information has not been translated into effective treatments. As MODS affects specific vascular beds, (organotypic) endothelial heterogeneity may be an important contributing factor to this lack of success. On the other hand, given the involvement of ECs in sepsis, this heterogeneity could also be leveraged for therapeutic gain to target specific sites of the vasculature given its full accessibility to drugs. In this review, we describe current knowledge that defines heterogeneity of organ-specific microvascular ECs at the molecular level and elaborate on studies that have reported EC responses across organ systems in sepsis patients and animal models of sepsis. We discuss hypothesis-driven, single-molecule studies that have formed the basis of our understanding of endothelial cell engagement in sepsis pathophysiology, and include recent studies employing high-throughput technologies. The latter deliver comprehensive data sets to describe molecular signatures for organotypic ECs that could lead to new hypotheses and form the foundation for rational pharmacological intervention and biomarker panel development. Particularly results from single cell RNA sequencing and spatial transcriptomics studies are eagerly awaited as they are expected to unveil the full spatiotemporal signature of EC responses to sepsis. With increasing awareness of the existence of distinct sepsis subphenotypes, and the need to develop new drug regimen and companion diagnostics, a better understanding of the molecular pathways exploited by ECs in sepsis pathophysiology will be a cornerstone to halt the detrimental processes that lead to MODS.
Collapse
Affiliation(s)
- Audrey Cleuren
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
| | - Grietje Molema
- Department Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| |
Collapse
|
|
8
|
Rashid A, Brusletto BS, Al-Obeidat F, Toufiq M, Benakatti G, Brierley J, Malik ZA, Hussain Z, Alkhazaimi H, Sharief J, Kadwa R, Sarpal A, Chaussabel D, Malik RA, Quraishi N, Khilnani P, Zaki SA, Nadeem R, Shaikh G, Al-Dubai A, Hafez W, Hussain A. A TRANSCRIPTOMIC APPRECIATION OF CHILDHOOD MENINGOCOCCAL AND POLYMICROBIAL SEPSIS FROM A PRO-INFLAMMATORY AND TRAJECTORIAL PERSPECTIVE, A ROLE FOR VASCULAR ENDOTHELIAL GROWTH FACTOR A AND B MODULATION? Shock 2023; 60:503-516. [PMID: 37553892 PMCID: PMC10581425 DOI: 10.1097/shk.0000000000002192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/12/2023] [Accepted: 07/19/2023] [Indexed: 08/10/2023]
Abstract
ABSTRACT This study investigated the temporal dynamics of childhood sepsis by analyzing gene expression changes associated with proinflammatory processes. Five datasets, including four meningococcal sepsis shock (MSS) datasets (two temporal and two longitudinal) and one polymicrobial sepsis dataset, were selected to track temporal changes in gene expression. Hierarchical clustering revealed three temporal phases: early, intermediate, and late, providing a framework for understanding sepsis progression. Principal component analysis supported the identification of gene expression trajectories. Differential gene analysis highlighted consistent upregulation of vascular endothelial growth factor A (VEGF-A) and nuclear factor κB1 (NFKB1), genes involved in inflammation, across the sepsis datasets. NFKB1 gene expression also showed temporal changes in the MSS datasets. In the postmortem dataset comparing MSS cases to controls, VEGF-A was upregulated and VEGF-B downregulated. Renal tissue exhibited higher VEGF-A expression compared with other tissues. Similar VEGF-A upregulation and VEGF-B downregulation patterns were observed in the cross-sectional MSS datasets and the polymicrobial sepsis dataset. Hexagonal plots confirmed VEGF-R (VEGF receptor)-VEGF-R2 signaling pathway enrichment in the MSS cross-sectional studies. The polymicrobial sepsis dataset also showed enrichment of the VEGF pathway in septic shock day 3 and sepsis day 3 samples compared with controls. These findings provide unique insights into the dynamic nature of sepsis from a transcriptomic perspective and suggest potential implications for biomarker development. Future research should focus on larger-scale temporal transcriptomic studies with appropriate control groups and validate the identified gene combination as a potential biomarker panel for sepsis.
Collapse
Affiliation(s)
- Asrar Rashid
- School of Computing, Edinburgh Napier University, Edinburgh, United Kingdom
- NMC Royal Hospital, Abu Dhabi, United Arab Emirates
| | - Berit S. Brusletto
- The Blood Cell Research Group, Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Norway
| | - Feras Al-Obeidat
- College of Technological Innovation at Zayed University, Abu Dhabi, United Arab Emirates
| | - Mohammed Toufiq
- The Jackson Laboratory for Genomic Medicine Farmington, Connecticut, USA
| | - Govind Benakatti
- Medanta Gururam, Delhi, India
- Yas Clinic, Abu Dhabi, United Arab Emirates
| | - Joe Brierley
- Great Ormond Street Children's Hospital, London, United Kingdom
| | - Zainab A. Malik
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Zain Hussain
- Edinburgh Medical School, University go Edinburgh, Edinburgh, United Kingdom
| | | | | | - Raziya Kadwa
- NMC Royal Hospital, Abu Dhabi, United Arab Emirates
| | - Amrita Sarpal
- Sidra Medicine, Doha, Qatar
- Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Damien Chaussabel
- The Jackson Laboratory for Genomic Medicine Farmington, Connecticut, USA
| | - Rayaz A. Malik
- Weill Cornell Medicine-Qatar, Doha, Qatar
- Institute of Cardiovascular Science, University of Manchester, Manchester, United Kingdom
| | - Nasir Quraishi
- Centre for Spinal Studies & Surgery, Queen's Medical Centre, The University of Nottingham, Nottingham, United Kingdom
| | | | - Syed A. Zaki
- All India Institute of Medical Sciences, Hyderabad, India
| | | | - Guftar Shaikh
- Endocrinology, Royal Hospital for Children, Glasgow, United Kingdom
| | - Ahmed Al-Dubai
- School of Computing, Edinburgh Napier University, Edinburgh, United Kingdom
| | - Wael Hafez
- NMC Royal Hospital, Abu Dhabi, United Arab Emirates
- Medical Research Division, Department of Internal Medicine, The National Research Centre, Cairo, Egypt
| | - Amir Hussain
- School of Computing, Edinburgh Napier University, Edinburgh, United Kingdom
| |
Collapse
|
|
9
|
Pinheiro da Silva F, Gonçalves ANA, Duarte‐Neto AN, Dias TL, Barbeiro HV, Breda CNS, Breda LCD, Câmara NOS, Nakaya HI. Transcriptome analysis of six tissues obtained post-mortem from sepsis patients. J Cell Mol Med 2023; 27:3157-3167. [PMID: 37731199 PMCID: PMC10568675 DOI: 10.1111/jcmm.17938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 08/16/2023] [Accepted: 08/22/2023] [Indexed: 09/22/2023] Open
Abstract
Septic shock is a life-threatening clinical condition characterized by a robust immune inflammatory response to disseminated infection. Little is known about its impact on the transcriptome of distinct human tissues. To address this, we performed RNA sequencing of samples from the prefrontal cortex, hippocampus, heart, lung, kidney and colon of seven individuals who succumbed to sepsis and seven uninfected controls. We identified that the lungs and colon were the most affected organs. While gene activation dominated, strong inhibitory signals were also detected, particularly in the lungs. We found that septic shock is an extremely heterogeneous disease, not only when different individuals are investigated, but also when comparing different tissues of the same patient. However, several pathways, such as respiratory electron transport and other metabolic functions, revealed distinctive alterations, providing evidence that tissue specificity is a hallmark of sepsis. Strikingly, we found evident signals of accelerated ageing in our sepsis population.
Collapse
Affiliation(s)
| | | | | | | | - Hermes Vieira Barbeiro
- Laboratório de Emergências Clínicas, Faculdade de MedicinaUniversidade de São PauloSão PauloBrazil
| | | | | | | | - Helder I. Nakaya
- Faculdade de Ciências FarmacêuticasUniversidade de São PauloSão PauloBrazil
- Hospital Israelita Albert EinsteinSão PauloBrazil
| |
Collapse
|
|
10
|
Long Q, Li G, Dong Q, Wang M, Li J, Wang L. Landscape of co-expressed genes between the myocardium and blood in sepsis and ceRNA network construction: a bioinformatic approach. Sci Rep 2023; 13:6221. [PMID: 37069215 PMCID: PMC10110604 DOI: 10.1038/s41598-023-33602-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/15/2023] [Indexed: 04/19/2023] Open
Abstract
Septic cardiomyopathy is a serious complication of sepsis. The mechanism of disease pathogenesis, which is caused by infection, is well researched. Despite ongoing efforts, there are no viable biological markers in the peripheral blood for early detection and diagnosis of septic cardiomyopathy. We aimed to uncover potential biomarkers of septic cardiomyopathy by comparing the covaried genes and pathways in the blood and myocardium of sepsis patients. Gene expression profiling of GSE79962, GSE65682, GSE54514, and GSE134364 was retrieved from the GEO database. Student's t-test was used for differential expression analysis. K-means clustering analysis was applied for subgroup identification. Least absolute shrinkage and selection operator (LASSO) and logistic regression were utilized for screening characteristic genes and model construction. Receiver operating characteristic (ROC) curves were generated for estimating the diagnostic efficacy. For ceRNA information prediction, miWalk and lncBase were applied. Cytoscape was used for ceRNA network construction. Inflammation-associated genes were upregulated, while genes related to mitochondria and aerobic metabolism were downregulated in both blood and the myocardium. Three groups with a significantly different mortality were identified by these covaried genes, using clustering analysis. Five characteristic genes-BCL2A1, CD44, ADGRG1, TGIF1, and ING3-were identified, which enabled the prediction of mortality of sepsis. The pathophysiological changes in the myocardium of patients with sepsis were also reflected in peripheral blood to some extent. The co-occurring pathological processes can affect the prognosis of sepsis. Thus, the genes we identified have the potential to become biomarkers for septic cardiomyopathy.
Collapse
Affiliation(s)
- Qi Long
- Department of Critical Care Medicine, Hubei Province Hospital of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China.
- Hubei Province Academy of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China.
| | - Gang Li
- Department of Critical Care Medicine, Hubei Province Hospital of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China
- Hubei Province Academy of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China
| | - Qiufen Dong
- Department of Critical Care Medicine, Hubei Province Hospital of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China
- Hubei Province Academy of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China
| | - Min Wang
- Department of Critical Care Medicine, Hubei Province Hospital of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China
- Hubei Province Academy of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China
| | - Jin Li
- Department of Critical Care Medicine, Hubei Province Hospital of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China
- Hubei Province Academy of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China
| | - Liulin Wang
- Department of Critical Care Medicine, Hubei Province Hospital of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China
- Hubei Province Academy of Traditional Chinese Medicine, 856 Luoyu Street, Wuhan, 430061, Hubei, People's Republic of China
| |
Collapse
|
|
11
|
Kidwell A, Yadav SPS, Maier B, Zollman A, Ni K, Halim A, Janosevic D, Myslinski J, Syed F, Zeng L, Waffo AB, Banno K, Xuei X, Doud EH, Dagher PC, Hato T. Translation Rescue by Targeting Ppp1r15a through Its Upstream Open Reading Frame in Sepsis-Induced Acute Kidney Injury in a Murine Model. J Am Soc Nephrol 2023; 34:220-240. [PMID: 36283811 PMCID: PMC10103092 DOI: 10.1681/asn.2022060644] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 09/23/2022] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Translation shutdown is a hallmark of late-phase, sepsis-induced kidney injury. Methods for controlling protein synthesis in the kidney are limited. Reversing translation shutdown requires dephosphorylation of the eukaryotic initiation factor 2 (eIF2) subunit eIF2 α ; this is mediated by a key regulatory molecule, protein phosphatase 1 regulatory subunit 15A (Ppp1r15a), also known as GADD34. METHODS To study protein synthesis in the kidney in a murine endotoxemia model and investigate the feasibility of translation control in vivo by boosting the protein expression of Ppp1r15a, we combined multiple tools, including ribosome profiling (Ribo-seq), proteomics, polyribosome profiling, and antisense oligonucleotides, and a newly generated Ppp1r15a knock-in mouse model and multiple mutant cell lines. RESULTS We report that translation shutdown in established sepsis-induced kidney injury is brought about by excessive eIF2 α phosphorylation and sustained by blunted expression of the counter-regulatory phosphatase Ppp1r15a. We determined the blunted Ppp1r15a expression persists because of the presence of an upstream open reading frame (uORF). Overcoming this barrier with genetic and antisense oligonucleotide approaches enabled the overexpression of Ppp1r15a, which salvaged translation and improved kidney function in an endotoxemia model. Loss of this uORF also had broad effects on the composition and phosphorylation status of the immunopeptidome-peptides associated with the MHC-that extended beyond the eIF2 α axis. CONCLUSIONS We found Ppp1r15a is translationally repressed during late-phase sepsis because of the existence of an uORF, which is a prime therapeutic candidate for this strategic rescue of translation in late-phase sepsis. The ability to accurately control translation dynamics during sepsis may offer new paths for the development of therapies at codon-level precision. PODCAST This article contains a podcast at.
Collapse
Affiliation(s)
- Ashley Kidwell
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Bernhard Maier
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Amy Zollman
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kevin Ni
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Arvin Halim
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Danielle Janosevic
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jered Myslinski
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Farooq Syed
- Department of Pediatrics and the Herman B. Wells Center, Indiana University School of Medicine, Indianapolis, Indiana
| | - Lifan Zeng
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Alain Bopda Waffo
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kimihiko Banno
- Department of Physiology, Nara Medical University, Kashihara, Japan
| | - Xiaoling Xuei
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Emma H. Doud
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Pierre C. Dagher
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Takashi Hato
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
- Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana
| |
Collapse
|
|
12
|
Brusletto BS, Hellerud BC, Olstad OK, Øvstebø R, Brandtzaeg P. Transcriptomic changes in the large organs in lethal meningococcal shock are reflected in a porcine shock model. Front Cell Infect Microbiol 2022; 12:908204. [PMID: 36034711 PMCID: PMC9413276 DOI: 10.3389/fcimb.2022.908204] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 07/06/2022] [Indexed: 11/26/2022] Open
Abstract
Background Fulminant meningococcal sepsis with shock and multiple organ failure is associated with a massive systemic inflammatory response involving solid organs. We have previously established a porcine model of the disease to study pathophysiologic and possible therapeutic strategies. Objective This study examined whether the organ specific gene expression profile in such a large animal model reflects the profile seen in patients with fulminant meningococcal sepsis. Patients and methods Data from gene expression profiles induced in organs from patients (n=5) and the porcine model (n=8) were imported into the Ingenuity pathway analysis (IPA) software for comparison analysis. The number of meningococci in the organs were quantified by real time-PCR. Results The all-over transcriptional activation between different organs revealed a striking concordance between the patients and the pigs regarding the pattern of transcriptional activation and activated pathways. Comparison analysis demonstrated similar pattern of upregulation of genes being associated with a large range of inflammatory biofunctions in the patients and the porcine model. Genes associated with biofunctions such as organismal death, morbidity and mortality were similarly downregulated in the patients and the porcine model. Comparison analysis of main predicted canonical pathways also demonstrated a high degree of similarity regarding up- and downregulation in both groups. Core analysis revealed different top-upstream regulators in the different organs in the patients. In the patients pro-inflammatory regulators were most activated in the lungs. In the other organs up-stream factors that regulate signaling pathways involved in development, growth, repair and homeostasis and triglyceride synthesis were most activated. In the porcine model, the top-upstream regulators were pro-inflammatory in all organs. The difference may reflect the shorter duration of the porcine experiment than the duration of the patient’s infection before death. Conclusion The inflammatory responses measured on the transcriptomic level in organs in patients with fulminant meningococcal sepsis is reproduced in the porcine model of the disease, although some differences may exist regarding the top-upregulated factors in individual organs. Thus, this large animal model reproduces important immunological features of meningococcal sepsis and can be a valuable tool in further investigations of inflammatory aspects and possible treatment options
Collapse
Affiliation(s)
- Berit Sletbakk Brusletto
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
- *Correspondence: Berit Sletbakk Brusletto,
| | | | | | - Reidun Øvstebø
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Petter Brandtzaeg
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
- Department of Pediatrics, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| |
Collapse
|
|
13
|
Exploration of the Shared Gene Signatures between Myocardium and Blood in Sepsis: Evidence from Bioinformatics Analysis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3690893. [PMID: 35971449 PMCID: PMC9375705 DOI: 10.1155/2022/3690893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 07/11/2022] [Accepted: 07/21/2022] [Indexed: 11/23/2022]
Abstract
Background Septic cardiomyopathy is widespread during sepsis and has adverse effects on mortality. Diagnosis of septic cardiomyopathy now mainly depends on transthoracic echocardiogram. Although some laboratory tests such as troponin T and atrial brain natriuretic peptide play a role in the diagnosis, specific blood biochemistry biomarkers are still lacking. Objective and Methods. In our study, we sought to find potential biological markers from genes and pathways that are covariant in the blood and myocardium of septic patients. Bioinformatics and machine learning methods were applied to achieve our goal. Datasets of myocardium and peripheral blood of patients with sepsis were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were selected and received functional enrichment analysis. Unsupervised hierarchical clustering analysis was performed to identify the subtypes of sepsis. Random forest, lasso regression, and logistic regression were used for variable screening and model construction. Internal and external validation sets were applied to verify the efficiency of the model in classifying disease and predicting mortality. Results By defining significance for genes using Student's t-test, we obtained 1,049 genes commonly changed in both myocardium and blood of patients with sepsis. The upregulated genes (LogFC >0) were related to inflammation pathways, and downregulated (LogFC <0) genes were related to mitochondrial and aerobic metabolism. We divided 468 sepsis patients into two groups with different clinical result based on the mortality-related commonly changed genes (104 genes), using unsupervised hierarchical clustering analysis. In our validation datasets, a six-gene model (SMU1, CLIC3, SP100, ARHGAP25, DECR1, and TNS3) was obtained and proven to perform well in classifying groups and predicting mortality. Conclusion We have identified genes that have the potential to become biomarkers for septic cardiomyopathy. Additionally, the pathophysiological changes in the myocardium of patients with sepsis were also reflected in peripheral blood to some extent. The co-occurring pathological processes can affect the prognosis of sepsis.
Collapse
|
|
14
|
Sun X, Wu J, Liu L, Chen Y, Tang Y, Liu S, Chen H, Jiang Y, Liu Y, Yuan H, Lu Y, Chen Z, Cai J. Transcriptional switch of hepatocytes initiates macrophage recruitment and T-cell suppression in endotoxemia. J Hepatol 2022; 77:436-452. [PMID: 35276271 DOI: 10.1016/j.jhep.2022.02.028] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 02/06/2022] [Accepted: 02/17/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The liver plays crucial roles in the regulation of immune defense during acute systemic infections. However, the roles of liver cellular clusters and intercellular communication in the progression of endotoxemia have not been well-characterized. METHODS Single-cell RNA sequencing analysis was performed, and the transcriptomes of 19,795 single liver cells from healthy and endotoxic mice were profiled. The spatial and temporal changes in hepatocytes and non-parenchymal cell types were validated by multiplex immunofluorescence staining, bulk transcriptomic sequencing, or flow cytometry. Furthermore, we used an adeno-associated virus delivery system to confirm the major mechanisms mediating myeloid cell infiltration and T-cell suppression in septic murine liver. RESULTS We identified a proinflammatory hepatocyte (PIH) subpopulation that developed primarily from periportal hepatocytes and to a lesser extent from pericentral hepatocytes and played key immunoregulatory roles in endotoxemia. Multicellular cluster modeling of ligand-receptor interactions revealed that PIHs play a crucial role in the recruitment of macrophages via the CCL2-CCR2 interaction. Recruited macrophages (RMs) released cytokines (e.g., IL6, TNFα, and IL17) to induce the expression of inhibitory ligands, such as PD-L1, on hepatocytes. Subsequently, RM-stimulated hepatocytes led to the suppression of CD4+ and memory T-cell subsets partly via the PD-1/PD-L1 interaction in endotoxemia. Furthermore, sinusoidal endothelial cells expressed the highest levels of proapoptotic and inflammatory genes around the periportal zone. This pattern of gene expression facilitated increases in the number of fenestrations and infiltration of immune cells in the periportal zone. CONCLUSIONS Our study elucidates unanticipated aspects of the cellular and molecular effects of endotoxemia on liver cells at the single-cell level and provides a conceptual framework for the development of novel therapeutic approaches for acute infection. LAY SUMMARY The liver plays a crucial role in the regulation of immune defense during acute systemic infections. We identified a proinflammatory hepatocyte subpopulation and demonstrated that the interactions of this subpopulation with recruited macrophages are pivotal in the immune response during endotoxemia. These novel findings provide a conceptual framework for the discovery of rational therapeutic targets in acute infection.
Collapse
Affiliation(s)
- Xuejing Sun
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Junru Wu
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Lun Liu
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yuanyuan Chen
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yan Tang
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Suzhen Liu
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Hang Chen
- Department of Cardiology, Fujian Medical Center for Cardiovascular Diseases, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China
| | - Youxiang Jiang
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yuanyuan Liu
- The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Hong Yuan
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China; The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yao Lu
- The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Zhaoyang Chen
- Department of Cardiology, Fujian Medical Center for Cardiovascular Diseases, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China.
| | - Jingjing Cai
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China; The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| |
Collapse
|
|
15
|
Zhao N, Zhang B, Jia L, He X, Bao B. Extracellular vesicles piwi-interacting RNAs from skin mucus for identification of infected Cynoglossus semilaevis with Vibrio harveyi. FISH & SHELLFISH IMMUNOLOGY 2021; 111:170-178. [PMID: 33561561 DOI: 10.1016/j.fsi.2021.02.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/28/2021] [Accepted: 02/02/2021] [Indexed: 06/12/2023]
Abstract
Extracellular vesicles play a regulatory role in intracellular and intercellular transmission through a variety of biological information molecules, including mRNA, small RNAs and proteins. piRNAs are one kind of regulatory small RNAs in the vesicles at the post transcriptional level. Hereby, we isolated the extracellular vesicles from skin mucus and screened the piRNA profiles of these vesicles, aiming at developing biomarkers related to bacterial infections in Cynoglossus semilaevis. The different profilings of piRNAs in mucous extracellular vesicles of C. semilaevis were compared through small RNA sequencing, between fish infected with Vibrio harveyi and healthy ones. The number of clean reads on the alignment of exosome sick (ES) group was 105, 345 and that of exosome control (EC) group was 455, 144. GO and KEGG pathway enrichment analysis showed that most of the target genes were involved in cellular process, response to stimulus, biological regulation, immune system process and signal transduction, signal molecular and interaction, transport and catabolism. The 45 final candidate piRNAs related to immunity or infectious diseases included 20 piRNAs with high expression in the ES group and 25 piRNAs with a low expression in the ES group. After verification by qRT-PCR, there was significant difference of five piRNAs expression level between infected fish and healthy fish, in line with the sequencing. The expression level of piR-mmu-16401212, piR-mmu-26829319 and piR-gga-244092 in infected fish were significantly lower than that of control group, while piR-gga-71717 and piR-gga-99034 were higher, which implying that these piRNAs in mucous extracellular vesicles can be used to identify diseased fish from normal ones. This work supplied a novel class of biomarker for infection diagnosis in fish, and it will be benefit for screening disease resistant breeding of C. semilaevis.
Collapse
Affiliation(s)
- Na Zhao
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China; International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, China
| | - Bo Zhang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China; International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, China; Tianjin Fisheries Research Institute, Tianjin, China.
| | - Lei Jia
- Tianjin Fisheries Research Institute, Tianjin, China
| | - Xiaoxu He
- Tianjin Fisheries Research Institute, Tianjin, China
| | - Baolong Bao
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China; International Research Center for Marine Biosciences at Shanghai Ocean University, Ministry of Science and Technology, China; National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, 201306, China.
| |
Collapse
|