Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance – ScienceOpen
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      Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance

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          Abstract

          Objective

          Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine.

          Design

          We performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples.

          Results

          We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease.

          Conclusion

          Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn’s disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.

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          Most cited references54

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          A general framework for weighted gene co-expression network analysis.

          Gene co-expression networks are increasingly used to explore the system-level functionality of genes. The network construction is conceptually straightforward: nodes represent genes and nodes are connected if the corresponding genes are significantly co-expressed across appropriately chosen tissue samples. In reality, it is tricky to define the connections between the nodes in such networks. An important question is whether it is biologically meaningful to encode gene co-expression using binary information (connected=1, unconnected=0). We describe a general framework for ;soft' thresholding that assigns a connection weight to each gene pair. This leads us to define the notion of a weighted gene co-expression network. For soft thresholding we propose several adjacency functions that convert the co-expression measure to a connection weight. For determining the parameters of the adjacency function, we propose a biologically motivated criterion (referred to as the scale-free topology criterion). We generalize the following important network concepts to the case of weighted networks. First, we introduce several node connectivity measures and provide empirical evidence that they can be important for predicting the biological significance of a gene. Second, we provide theoretical and empirical evidence that the ;weighted' topological overlap measure (used to define gene modules) leads to more cohesive modules than its ;unweighted' counterpart. Third, we generalize the clustering coefficient to weighted networks. Unlike the unweighted clustering coefficient, the weighted clustering coefficient is not inversely related to the connectivity. We provide a model that shows how an inverse relationship between clustering coefficient and connectivity arises from hard thresholding. We apply our methods to simulated data, a cancer microarray data set, and a yeast microarray data set.
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            Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

            Crohn’s disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry with rising prevalence in other populations 1 . Genome-wide association studies (GWAS) and subsequent meta-analyses of CD and UC 2,3 as separate phenotypes implicated previously unsuspected mechanisms, such as autophagy 4 , in pathogenesis and showed that some IBD loci are shared with other inflammatory diseases 5 . Here we expand knowledge of relevant pathways by undertaking a meta-analysis of CD and UC genome-wide association scans, with validation of significant findings in more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional and balancing selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe striking overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
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              Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors

              Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C+ subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease.
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                Author and article information

                Journal
                Gut
                Gut
                gutjnl
                gut
                Gut
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0017-5749
                1468-3288
                June 2021
                9 October 2020
                : 70
                : 6
                : 1023-1036
                Affiliations
                [1 ] departmentTranslational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital , University of Oxford , Oxford, Oxfordshire, UK
                [2 ] departmentIBD Center, Laboratory of Gastrointestinal Immunopathology , Humanitas Clinical and Research Center , Milan, Italy
                [3 ] departmentDepartment of Psychology , University of Cambridge , Cambridge, Cambridgeshire, UK
                [4 ] departmentKennedy Institute of Rheumatology , University of Oxford , Oxford, Oxfordshire, UK
                [5 ] departmentWolfson Centre for Mathematical Biology , University of Oxford , Oxford, Oxfordshire, UK
                [6 ] departmentImmunology Translational Sciences , Eli Lilly and Company , Indianapolis, Indiana, USA
                [7 ] departmentPediatric Gastroenterology , Cincinnati Childrens Hospital Medical Center , Cincinnati, Ohio, USA
                [8 ] departmentPediatrics , Emory University School of Medicine , Atlanta, Georgia, USA
                [9 ] departmentDepartment of Paediatrics , University of Oxford , Oxford, Oxfordshire, UK
                Author notes
                [Correspondence to ] Professor Holm H Uhlig, Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, Oxfordshire, UK; holm.uhlig@ 123456ndm.ox.ac.uk

                SNS and HHU are joint senior authors.

                DA and MQ are joint first authors.

                Author information
                http://orcid.org/0000-0001-7580-2567
                http://orcid.org/0000-0001-7748-9885
                http://orcid.org/0000-0002-6111-7355
                Article
                gutjnl-2020-321731
                10.1136/gutjnl-2020-321731
                8108288
                33037057
                2ebe6ff4-855c-465d-a733-05d3cb3eb71c
                © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

                History
                : 06 May 2020
                : 16 July 2020
                : 28 August 2020
                Funding
                Funded by: http://dx.doi.org/10.13039/100004312, Eli Lilly and Company;
                Award ID: HBRYHG00
                Funded by: Wellcome Trust;
                Award ID: 212240/Z/18/Z
                Categories
                Inflammatory Bowel Disease
                1506
                2312
                Original research
                Custom metadata
                unlocked

                Gastroenterology & Hepatology
                mucosal immunology,inflammatory bowel disease,interleukins
                Gastroenterology & Hepatology
                mucosal immunology, inflammatory bowel disease, interleukins

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