TY - JOUR AU - Sampson, O.L. AU - Jay, C. AU - Adland, E. AU - Csala, A. AU - Lim, N. AU - Ebbrecht, S.M. AU - Gilligan, L.C. AU - Taylor, A.E. AU - George, S.S. AU - Longet, S. AU - Jones, L.C. AU - Barnes, E. AU - Frater, J. AU - Klenerman, P. AU - Dunachie, S. AU - Carrol, M. AU - Hawley, J. AU - Arlt, W. AU - Groll, A. AU - Goulder, P. TI - Gonadal androgens are associated with decreased type I interferon production by plasmacytoid dendritic cells and increased IgG titres to BNT162b2 following co-vaccination with live attenuated influenza vaccine in adolescents JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 PG - 12 SN - 1664-3224 DO - 10.3389/fimmu.2024.1329805 UR - https://m2.mtmt.hu/api/publication/34820290 ID - 34820290 N1 - Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom Department of Statistics, Technical University of Dortmund, Dortmund, Germany Steroid Metabolome Analysis Core, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom Biochemistry Department, Clinical Science Building, Wythenshawe Hospital, Manchester, United Kingdom Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom Department of Microbiology, Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom Medical Research Council London Institute of Medical Sciences (MRC LMS), Imperial College London, London, United Kingdom CIRI - Centre International de Recherche en Infectiologie, Team GIMAP (Saint-Etienne), Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, UJM, Lyon, France Export Date: 25 April 2024; Cited By: 0; Correspondence Address: P. Goulder; Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom; email: philip.goulder@paediatrics.ox.ac.uk AB - mRNA vaccine technologies introduced following the SARS-CoV-2 pandemic have highlighted the need to better understand the interaction of adjuvants and the early innate immune response. Type I interferon (IFN-I) is an integral part of this early innate response that primes several components of the adaptive immune response. Women are widely reported to respond better than men to tri- and quadrivalent influenza vaccines. Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production, and female pDCs produce more IFN-I than male pDCs since the upstream pattern recognition receptor Toll-like receptor 7 (TLR7) is encoded by X chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains several putative androgen response elements, and androgens have been reported to suppress pDC IFN-I in vitro. Unexpectedly, therefore, we recently observed that male adolescents mount stronger antibody responses to the Pfizer BNT162b2 mRNA vaccine than female adolescents after controlling for natural SARS-CoV-2 infection. We here examined pDC behaviour in this same cohort to determine the impact of IFN-I on anti-spike and anti-receptor-binding domain IgG titres to BNT162b2. Through flow cytometry and least absolute shrinkage and selection operator (LASSO) modelling, we determined that serum-free testosterone was associated with reduced pDC IFN-I, but contrary to the well-described immunosuppressive role for androgens, the most bioactive androgen dihydrotestosterone was associated with increased IgG titres to BNT162b2. Also unexpectedly, we observed that co-vaccination with live attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together, these data support a model where systemic IFN-I increases vaccine-mediated immune responses, yet for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently improve vaccine-driven immunity. Copyright © 2024 Sampson, Jay, Adland, Csala, Lim, Ebbrecht, Gilligan, Taylor, George, Longet, Jones, Barnes, Frater, Klenerman, Dunachie, Carrol, Hawley, Arlt, Groll and Goulder. LA - English DB - MTMT ER - TY - JOUR AU - Yuan, Weichen AU - Li, Xiangrui AU - Wang, Guan AU - Qu, Bo AU - Zhao, Fangkun TI - Association of autoimmune and allergic diseases with senile cataract: a bidirectional two-sample Mendelian randomization study JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 PG - 11 SN - 1664-3224 DO - 10.3389/fimmu.2024.1325868 UR - https://m2.mtmt.hu/api/publication/34819623 ID - 34819623 LA - English DB - MTMT ER - TY - JOUR AU - Seiringer, Peter AU - Hillig, Christina AU - Schäbitz, Alexander AU - Jargosch, Manja AU - Pilz, Anna Caroline AU - Eyerich, Stefanie AU - Szegedi, Andrea AU - Sochorová, Michaela AU - Gruber, Florian AU - Zouboulis, Christos C. AU - Biedermann, Tilo AU - Menden, Michael P. AU - Eyerich, Kilian AU - Törőcsik, Dániel TI - Spatial transcriptomics reveals altered lipid metabolism and inflammation-related gene expression of sebaceous glands in psoriasis and atopic dermatitis JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 SN - 1664-3224 DO - 10.3389/fimmu.2024.1334844 UR - https://m2.mtmt.hu/api/publication/34819371 ID - 34819371 AB - Sebaceous glands drive acne, however, their role in other inflammatory skin diseases remains unclear. To shed light on their potential contribution to disease development, we investigated the spatial transcriptome of sebaceous glands in psoriasis and atopic dermatitis patients across lesional and non-lesional human skin samples. Both atopic dermatitis and psoriasis sebaceous glands expressed genes encoding key proteins for lipid metabolism and transport such as ALOX15B, APOC1, FABP7, FADS1/2, FASN, PPARG , and RARRES1. Also, inflammation-related SAA1 was identified as a common spatially variable gene. In atopic dermatitis, genes mainly related to lipid metabolism (e.g. ACAD8, FADS6 , or EBP) as well as disease-specific genes, i.e., Th2 inflammation-related lipid-regulating HSD3B1 were differentially expressed. On the contrary, in psoriasis, more inflammation-related spatially variable genes (e.g. SERPINF1 , FKBP5 , IFIT1/3, DDX58 ) were identified. Other psoriasis-specific enriched pathways included lipid metabolism (e.g. ACOT4, S1PR3) , keratinization (e.g. LCE5A, KRT5/7/16 ), neutrophil degranulation, and antimicrobial peptides (e.g. LTF, DEFB4A, S100A7-9 ). In conclusion, our results show that sebaceous glands contribute to skin homeostasis with a cell type-specific lipid metabolism, which is influenced by the inflammatory microenvironment. These findings further support that sebaceous glands are not bystanders in inflammatory skin diseases, but can actively and differentially modulate inflammation in a disease-specific manner. LA - English DB - MTMT ER - TY - JOUR AU - Liu, Wenbin AU - Wang, Xiaofeng AU - Zhao, Shanzhi AU - Yang, Song AU - Zheng, Xiangtao AU - Gong, Fangchen AU - Pei, Lei AU - Xu, Dan AU - Li, Ranran AU - Yang, Zhitao AU - Mao, Enqiang AU - Chen, Erzhen AU - Chen, Ying TI - Unraveling the immunological landscape in acute pancreatitis progression to sepsis: insights from a Mendelian randomization study on immune cell traits JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 PG - 10 SN - 1664-3224 DO - 10.3389/fimmu.2024.1374787 UR - https://m2.mtmt.hu/api/publication/34818947 ID - 34818947 N1 - Funding Agency and Grant Number: Shanghai Shenkang Hospital Development Center Clinical Science and Technology Innovation Project [SHDC22022201, SHDC22021304]; National Natural Science Foundation of China [82270087]; Shanghai Health Commission Project [202340068] Funding text: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by the following grants: Shanghai Shenkang Hospital Development Center Clinical Science and Technology Innovation Project (Grant No.SHDC22021304, No.SHDC22022201), National Natural Science Foundation of China (Grant No. 82270087), Shanghai Health Commission Project (Grant No.202340068). AB - Background Acute pancreatitis (AP) is a severe digestive system disorder with a significant risk of progressing to sepsis, a major cause of mortality. Unraveling the immunological pathways in AP is essential for developing effective treatments, particularly understanding the role of specific immune cell traits in this progression.Methods Employing a bidirectional two-sample Mendelian Randomization (MR) approach, this study first examined the causal relationship between AP and 731 immune cell traits to identify those significantly associated with AP. Subsequently, we explored the causal associations between 731 immune cell traits and sepsis. The analysis utilized extensive genome-wide association studies (GWAS) summary datasets, with a focus on identifying common immune cell traits with statistically significant causal associations between AP and sepsis.Results Our investigation identified 44 immune cell traits unidirectionally associated with AP and 36 traits unidirectionally associated with sepsis. Among these, CD127 on CD28+ CD45RA- CD8+ T cells emerged as a common mediator, accounting for 5.296% of the increased risk of sepsis in AP patients. This finding highlights the significant role of specific memory CD8+ T cells in the pathophysiology of AP and its progression to sepsis.Conclusion This study elucidates the critical role of specific immune cell traits, particularly CD127hi memory CD8+ T cells, in the progression of AP to sepsis. Our findings provide a foundation for future research into targeted immune-modulatory therapies, potentially improving patient outcomes in AP-related sepsis and offering new insights into the complex immunological dynamics of this condition. LA - English DB - MTMT ER - TY - JOUR AU - Baranova, A. AU - Luo, J. AU - Fu, L. AU - Yao, G. AU - Zhang, F. TI - Evaluating the effects of circulating inflammatory proteins as drivers and therapeutic targets for severe COVID-19 JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 SN - 1664-3224 DO - 10.3389/fimmu.2024.1352583 UR - https://m2.mtmt.hu/api/publication/34818059 ID - 34818059 N1 - School of Systems Biology, George Mason University, Manassas, VA, United States Research Centre for Medical Genetics, Moscow, Russian Federation Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China School of Medicine, Tsinghua University, Beijing, China Department of Psychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China School of Clinical Medicine, Tsinghua University, Beijing, China Institute of Neuropsychiatry, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China Export Date: 24 April 2024 Correspondence Address: Zhang, F.; Department of Psychiatry, China; email: zhangfq@njmu.edu.cn LA - English DB - MTMT ER - TY - JOUR AU - Otsuka, Y. AU - Minaga, K. AU - Kudo, M. AU - Watanabe, T. TI - Role of leucine-rich repeat kinase 2 in severe acute pancreatitis JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 SN - 1664-3224 DO - 10.3389/fimmu.2024.1364839 UR - https://m2.mtmt.hu/api/publication/34814887 ID - 34814887 N1 - Export Date: 23 April 2024 Correspondence Address: Watanabe, T.; Department of Gastroenterology and Hepatology, Osaka, Japan; email: tomohiro@med.kindai.ac.jp Chemicals/CAS: protein kinase Syk, 138674-26-7; toll like receptor 4, 203811-83-0; trypsinogen, 9002-08-8; leucine, 61-90-5, 7005-03-0; trypsin, 9002-07-7; Leucine; Trypsin Funding details: KD2301 Funding details: Takeda Science Foundation, TSF Funding details: Kindai University, KD2208 Funding details: Japan Society for the Promotion of Science, JSPS Funding details: Smoking Research Foundation, SRF Funding details: SENSHIN Medical Research Foundation, SMRF Funding details: Yakult Bio-Science Foundation, YBSF Funding text 1: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Grants-in-Aid for Scientific Research (22K07996) from the Japan Society for the Promotion of Science, Takeda Science Foundation, Smoking Research Foundation, Yakult Bio-Science Foundation, SENSHIN Medical Research Foundation, 2022 Kindai University Research Enhancement Grant (KD2208), and 2023 Kindai University Research Enhancement Grant (KD2301). Acknowledgments AB - Introduction: Intrapancreatic activation of trypsinogen caused by alcohol or high-fat intake and the subsequent autodigestion of the pancreas tissues by trypsin are indispensable events in the development of acute pancreatitis. In addition to this trypsin-centered paradigm, recent studies provide evidence that innate immune responses triggered by translocation of intestinal bacteria to the pancreas due to intestinal barrier dysfunction underlie the immunopathogenesis of acute pancreatitis. Although severe acute pancreatitis is often associated with pancreatic colonization by fungi, the molecular mechanisms linking fungus-induced immune responses to the development of severe acute pancreatitis are poorly understood. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that mediates innate immune responses to fungi and bacteria. Mutations in Lrrk2 is a risk factor for Parkinson’s disease and Crohn’s disease, both of which are driven by innate immune responses to gut organisms. Discussion: In this Minireview article, we discuss how activation of LRRK2 by the recognition of fungi induces severe acute pancreatitis. Copyright © 2024 Otsuka, Minaga, Kudo and Watanabe. LA - English DB - MTMT ER - TY - JOUR AU - Badia-Bringué, G. AU - Lavín, J.L. AU - Casais, R. AU - Alonso-Hearn, M. TI - Alternative splicing of pre-mRNA modulates the immune response in Holstein cattle naturally infected with Mycobacterium avium subsp. paratuberculosis JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 SN - 1664-3224 DO - 10.3389/fimmu.2024.1354500 UR - https://m2.mtmt.hu/api/publication/34814571 ID - 34814571 N1 - Department of Animal Health, NEIKER- Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Bizkaia, Derio, Spain Department of Applied Mathematics, NEIKER- Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), Bizkaia, Derio, Spain Center of Animal Biotechnology, Servicio Regional de Investigación y Desarrollo Agroalimentario (SERIDA), Deva, Spain Export Date: 23 April 2024 Correspondence Address: Alonso-Hearn, M.; Department of Animal Health, Bizkaia, Spain; email: malonso@neiker.eus Chemicals/CAS: cytochrome P450, 9035-51-2; RNA Precursors Tradenames: NEBNext Ultra, Illumina, United States; NextSeq 500, Illumina, United States; PX1, Biorad, United States; QX200, Biorad, United States; RNeasy Mini, Qiagen, Germany; RT2 First Strand, Qiagen, Germany; T100, Biorad, United States Manufacturers: Qiagen, Germany; Idexx, Netherlands; Biorad, United States; Illumina, United States Funding details: Institut National de la Recherche Agronomique, INRA Funding details: Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, INIA, MCIN/AEI/10.13039/501100011033, RTA2014-00009, RTI2018-094192, PID2021-122197OR Funding details: Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, INIA Funding details: Federación Española de Enfermedades Raras, FEDER, IDI2021-000102 Funding details: Federación Española de Enfermedades Raras, FEDER Funding details: Faculty of Science and Engineering, University of Manchester, FSE, PRE2019-090562 Funding details: Faculty of Science and Engineering, University of Manchester, FSE Funding text 1: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Financial support for this study was provided by the National Institute for Agricultural Research (INIA) (RTA2014-00009; RTI2018-094192, PID2021-122197OR), MCIN/AEI/10.13039/501100011033, and FEDER, “Una manera de hacer Europa”. Funds were also provided by the Gobierno del Principado de Asturias Regional funds PCTI 2021–2023 (GRUPIN: IDI2021-000102) co-funded by FEDER. GBB was awarded a fellowship from INIA and MCIN/AEI/10.13039/501100011033 and “FSE Invierte en tu futuro” (PRE2019-090562). Funding text 2: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Financial support for this study was provided by the National Institute for Agricultural Research (INIA) (RTA2014-00009; RTI2018-094192, PID2021-122197OR), MCIN/AEI/10.13039/501100011033, and FEDER, “Una manera de hacer Europa”. Funds were also provided by the Gobierno del Principado de Asturias Regional funds PCTI 2021–2023 (GRUPIN: IDI2021-000102) co-funded by FEDER. GBB was awarded a fellowship from INIA and MCIN/AEI/10.13039/501100011033 and “FSE Invierte en tu futuro” (PRE2019-090562). Acknowledgments AB - Little is known about the role of alternative splicing (AS) in regulating gene expression in Mycobacteria-infected individuals in distinct stages of infection. Pre-mRNA AS consists of the removal of introns and the assembly of exons contained in eukaryotic genes. AS events can influence transcript stability or structure with important physiological consequences. Using RNA-Seq data from peripheral blood (PB) and ileocecal valve (ICV) samples collected from Holstein cattle with focal and diffuse paratuberculosis (PTB)-associated histopathological lesions in gut tissues and without lesions (controls), we detected differential AS profiles between the infected and control groups. Four of the identified AS events were experimentally validated by reverse transcription-digital droplet PCR (RT-ddPCR). AS events in several genes correlated with changes in gene expression. In the ICV of animals with diffuse lesions, for instance, alternatively spliced genes correlated with changes in the expression of genes involved in endocytosis, antigen processing and presentation, complement activation, and several inflammatory and autoimmune diseases in humans. Taken together, our results identified common mechanisms of AS involvement in the pathogenesis of PTB and human diseases and shed light on novel diagnostic and therapeutic interventions to control these diseases. Copyright © 2024 Badia-Bringué, Lavín, Casais and Alonso-Hearn. LA - English DB - MTMT ER - TY - JOUR AU - Lang, R. AU - Siddique, M.N.A.A. TI - Control of immune cell signaling by the immuno-metabolite itaconate JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 SN - 1664-3224 DO - 10.3389/fimmu.2024.1352165 UR - https://m2.mtmt.hu/api/publication/34813404 ID - 34813404 N1 - Export Date: 23 April 2024 Correspondence Address: Lang, R.; Institute of Clinical Microbiology, Germany; email: roland.lang@uk-erlangen.de Chemicals/CAS: cysteine, 4371-52-2, 52-89-1, 52-90-4; glutathione, 70-18-8; itaconic acid, 97-65-4; lysine, 56-87-1, 6899-06-5, 70-54-2; itaconic acid; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Succinates Funding details: Johannes und Frieda Marohn-Stiftung Funding details: Deutsche Forschungsgemeinschaft, DFG, LA1262/8-1, CRC1181 TP A06, GRK 2599 Funding text 1: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Work in the Lang lab is supported by the Deutsche Forschungsgemeinschaft (LA1262/8-1; CRC1181 TP A06; GRK 2599) and by the Johannes und Frieda Marohn-Stiftung. AB - Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell’s metabolic activity to provide energy and biomolecules for inflammatory and proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns and cytokines upregulate expression of the enzyme ACOD1 that generates the immune-metabolite itaconate by decarboxylation of the TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well as immunomodulatory activities, which makes it attractive as endogenous effector metabolite fighting infection and restraining inflammation. Here, we first summarize the pathways and stimuli inducing ACOD1 expression in macrophages. The focus of the review then lies on the mechanisms by which itaconate, and its synthetic derivatives and endogenous isomers, modulate immune cell signaling and metabolic pathways. Multiple targets have been revealed, from inhibition of enzymes to the post-translational modification of many proteins at cysteine or lysine residues. The modulation of signaling proteins like STING, SYK, JAK1, RIPK3 and KEAP1, transcription regulators (e.g. Tet2, TFEB) and inflammasome components (NLRP3, GSDMD) provides a biochemical basis for the immune-regulatory effects of the ACOD1-itaconate pathway. While the field has intensely studied control of macrophages by itaconate in infection and inflammation models, neutrophils have now entered the scene as producers and cellular targets of itaconate. Furthermore, regulation of adaptive immune responses by endogenous itaconate, as well as by exogenously added itaconate and derivatives, can be mediated by direct and indirect effects on T cells and antigen-presenting cells, respectively. Taken together, research in ACOD1-itaconate to date has revealed its relevance in diverse immune cell signaling pathways, which now provides opportunities for potential therapeutic or preventive manipulation of host defense and inflammation. Copyright © 2024 Lang and Siddique. LA - English DB - MTMT ER - TY - JOUR AU - Kannan, K.P. AU - Girija, A.S S. TI - Exploring the ROS reduction strategies in chronic lupus management JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 SN - 1664-3224 DO - 10.3389/fimmu.2024.1346656 UR - https://m2.mtmt.hu/api/publication/34813378 ID - 34813378 N1 - Export Date: 23 April 2024 Correspondence Address: Girija A.S, S.; Department of Microbiology, Tamilnadu, India; email: smilinejames25@gmail.com Chemicals/CAS: acetylcysteine, 616-91-1; anifrolumab, 1326232-46-5; azathioprine, 446-86-6, 55774-33-9; catalase, 9001-05-2; cyclophosphamide, 50-18-0, 6055-19-2; gamma interferon, 82115-62-6; glutathione peroxidase, 9013-66-5; malonaldehyde, 542-78-9; methotrexate, 15475-56-6, 59-05-2, 7413-34-5, 7532-09-4, 6745-93-3, 51865-79-3, 60388-53-6; mycophenolate mofetil, 116680-01-4, 128794-94-5, 115007-34-6; myeloperoxidase; reduced nicotinamide adenine dinucleotide phosphate oxidase, 9032-22-8; rituximab, 174722-31-7; superoxide dismutase, 37294-21-6, 9016-01-7, 9054-89-1; toll like receptor 9, 352486-49-8, 390883-32-6; voclosporin, 515814-01-4; Reactive Oxygen Species Funding text 1: The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article. LA - English DB - MTMT ER - TY - JOUR AU - Yang, Q. AU - Langston, J.C. AU - Prosniak, R. AU - Pettigrew, S. AU - Zhao, H. AU - Perez, E. AU - Edelmann, H. AU - Mansoor, N. AU - Merali, C. AU - Merali, S. AU - Marchetti, N. AU - Prabhakarpandian, B. AU - Kiani, M.F. AU - Kilpatrick, L.E. TI - Distinct functional neutrophil phenotypes in sepsis patients correlate with disease severity JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 15 PY - 2024 SN - 1664-3224 DO - 10.3389/fimmu.2024.1341752 UR - https://m2.mtmt.hu/api/publication/34813263 ID - 34813263 N1 - Department of Mechanical Engineering, College of Engineering, Temple University, Philadelphia, PA, United States Department of Bioengineering, College of Engineering, Temple University, Philadelphia, PA, United States Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States Department of Biomedical Education and Data Science, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States Center for Inflammation and Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States School of Pharmacy, Temple University, Philadelphia, PA, United States Biomedical Technology, CFD Research Corporation, Huntsville, AL, United States Export Date: 23 April 2024 Correspondence Address: Kilpatrick, L.E.; Department of Thoracic Medicine and Surgery, United States; email: laurie.kilpatrick@temple.edu Chemicals/CAS: interleukin 8, 114308-91-7; Biomarkers Tradenames: Q Exactive, Thermo, United States Manufacturers: Thermo, United States Funding details: National Institutes of Health, NIH, GM134701, 1-F31AI164870-01 Funding details: National Institutes of Health, NIH Funding details: Defense Threat Reduction Agency, DTRA, HDTRA11910012 Funding details: Defense Threat Reduction Agency, DTRA Funding text 1: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported This work was supported by the National Institutes of Health, Grant Number: GM134701 (LK, MK) and Defense Threat Reduction Agency, Grant/Award Number: HDTRA11910012 (MK, LK). JL is an NIH NRSA F31 Predoctoral Fellow(1-F31AI164870-01). AB - Purpose: Sepsis is a clinical syndrome defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is a highly heterogeneous syndrome with distinct phenotypes that impact immune function and response to infection. To develop targeted therapeutics, immunophenotyping is needed to identify distinct functional phenotypes of immune cells. In this study, we utilized our Organ-on-Chip assay to categorize sepsis patients into distinct phenotypes using patient data, neutrophil functional analysis, and proteomics. Methods: Following informed consent, neutrophils and plasma were isolated from sepsis patients in the Temple University Hospital ICU (n=45) and healthy control donors (n=7). Human lung microvascular endothelial cells (HLMVEC) were cultured in the Organ-on-Chip and treated with buffer or cytomix ((TNF/IL-1β/IFNγ). Neutrophil adhesion and migration across HLMVEC in the Organ-on-Chip were used to categorize functional neutrophil phenotypes. Quantitative label-free global proteomics was performed on neutrophils to identify differentially expressed proteins. Plasma levels of sepsis biomarkers and neutrophil extracellular traps (NETs) were determined by ELISA. Results: We identified three functional phenotypes in critically ill ICU sepsis patients based on ex vivo neutrophil adhesion and migration patterns. The phenotypes were classified as: Hyperimmune characterized by enhanced neutrophil adhesion and migration, Hypoimmune that was unresponsive to stimulation, and Hybrid with increased adhesion but blunted migration. These functional phenotypes were associated with distinct proteomic signatures and differentiated sepsis patients by important clinical parameters related to disease severity. The Hyperimmune group demonstrated higher oxygen requirements, increased mechanical ventilation, and longer ICU length of stay compared to the Hypoimmune and Hybrid groups. Patients with the Hyperimmune neutrophil phenotype had significantly increased circulating neutrophils and elevated plasma levels NETs. Conclusion: Neutrophils and NETs play a critical role in vascular barrier dysfunction in sepsis and elevated NETs may be a key biomarker identifying the Hyperimmune group. Our results establish significant associations between specific neutrophil functional phenotypes and disease severity and identify important functional parameters in sepsis pathophysiology that may provide a new approach to classify sepsis patients for specific therapeutic interventions. Copyright © 2024 Yang, Langston, Prosniak, Pettigrew, Zhao, Perez, Edelmann, Mansoor, Merali, Merali, Marchetti, Prabhakarpandian, Kiani and Kilpatrick. LA - English DB - MTMT ER -