CRIg-expressing peritoneal macrophages are associated with disease severity in patients with cirrhosis and ascites.

Infections are an important cause of morbidity and mortality in patients with decompensated cirrhosis and ascites. Hypothesizing that innate immune dysfunction contributes to susceptibility to infection, we assessed ascitic fluid macrophage phenotype and function. The expression of complement receptor of the immunoglobulin superfamily (CRIg) and CCR2 defined two phenotypically and functionally distinct peritoneal macrophage subpopulations. The proportion of CRIghi macrophages differed between patients and in the same patient over time, and a high proportion of CRIghi macrophages was associated with reduced disease severity (model for end-stage liver disease) score. As compared with CRIglo macrophages, CRIghi macrophages were highly phagocytic and displayed enhanced antimicrobial effector activity. Transcriptional profiling by RNA sequencing and comparison with human macrophage and murine peritoneal macrophage expression signatures highlighted similarities among CRIghi cells, human macrophages, and mouse F4/80hi resident peritoneal macrophages and among CRIglo macrophages, human monocytes, and mouse F4/80lo monocyte-derived peritoneal macrophages. These data suggest that CRIghi and CRIglo macrophages may represent a tissue-resident population and a monocyte-derived population, respectively. In conclusion, ascites fluid macrophage subset distribution and phagocytic capacity is highly variable among patients with chronic liver disease. Regulating the numbers and/or functions of these macrophage populations could provide therapeutic opportunities in cirrhotic patients.

[1]  Pablo Tamayo,et al.  Compendium of Immune Signatures Identifies Conserved and Species-Specific Biology in Response to Inflammation. , 2016, Immunity.

[2]  D. Hume,et al.  CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure , 2015, Gastroenterology.

[3]  I. Choi,et al.  Endogenous VSIG4 negatively regulates the helper T cell-mediated antibody response. , 2015, Immunology letters.

[4]  K. Schroder,et al.  Strain- and host species-specific inflammasome activation, IL-1β release, and cell death in macrophages infected with uropathogenic Escherichia coli , 2015, Mucosal Immunology.

[5]  S. Verma,et al.  Long‐term outcomes after hospitalization with spontaneous bacterial peritonitis , 2015, Journal of digestive diseases.

[6]  K. Irvine,et al.  Ascites Bacterial Burden and Immune Cell Profile Are Associated with Poor Clinical Outcomes in the Absence of Overt Infection , 2015, PloS one.

[7]  C. Abbott,et al.  Protein Kinase Cα Regulates the Expression of Complement Receptor Ig in Human Monocyte–Derived Macrophages , 2015, The Journal of Immunology.

[8]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[9]  Yingwei Wang,et al.  A novel CRIg‐targeted complement inhibitor protects cells from complement damage , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  R. Nibbs,et al.  The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density , 2014, The EMBO journal.

[11]  S. Quezada,et al.  Resolution of acute inflammation bridges the gap between innate and adaptive immunity. , 2014, Blood.

[12]  Paul Theodor Pyl,et al.  HTSeq—a Python framework to work with high-throughput sequencing data , 2014, bioRxiv.

[13]  T. Sutherland,et al.  Host protective roles of type 2 immunity: Parasite killing and tissue repair, flip sides of the same coin , 2014, Seminars in immunology.

[14]  Maxim N. Artyomov,et al.  Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival , 2014, The Journal of experimental medicine.

[15]  G. Randolph,et al.  Origin and functions of tissue macrophages. , 2014, Immunity.

[16]  S. McPhail,et al.  Burden of decompensated cirrhosis and ascites on hospital services in a tertiary care facility: time for change? , 2014, Internal medicine journal.

[17]  Zachary D. Kurtz,et al.  Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct. , 2014, Blood.

[18]  P. Taylor,et al.  The Transcription Factor Gata6 Links Tissue Macrophage Phenotype and Proliferative Renewal , 2014, Science.

[19]  R. Medzhitov,et al.  Tissue-Specific Signals Control Reversible Program of Localization and Functional Polarization of Macrophages , 2014, Cell.

[20]  Andmorgan R. Fisher,et al.  Altered profile of human gut microbiome is associated with cirrhosis and its complications. , 2014, Journal of hepatology.

[21]  Tom C. Freeman,et al.  Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation , 2014, Immunity.

[22]  D. Hume,et al.  IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1 , 2013, The Journal of experimental medicine.

[23]  G. Randolph,et al.  Local apoptosis mediates clearance of macrophages from resolving inflammation in mice. , 2013, Blood.

[24]  P. Taylor,et al.  Distinct bone marrow-derived and tissue resident macrophage-lineages proliferate at key stages during inflammation , 2013, Nature Communications.

[25]  E. Murphy,et al.  The gut microbiota and the liver. Pathophysiological and clinical implications. , 2013, Journal of hepatology.

[26]  I. Han,et al.  CRIg signals induce anti‐intracellular bacterial phagosome activity in a chloride intracellular channel 3‐dependent manner , 2013, European journal of immunology.

[27]  V. Soumelis,et al.  Human inflammatory dendritic cells induce Th17 cell differentiation. , 2013, Immunity.

[28]  A. Mildner,et al.  Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. , 2013, Immunity.

[29]  L. Joosten,et al.  Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. , 2012, American journal of respiratory and critical care medicine.

[30]  I. Choi,et al.  Protective role of V‐set and immunoglobulin domain‐containing 4 expressed on kupffer cells during immune‐mediated liver injury by inducing tolerance of liver T‐ and natural killer T‐cells , 2012, Hepatology.

[31]  Amin R. Mazloom,et al.  Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages , 2012, Nature Immunology.

[32]  W. Huber,et al.  Detecting differential usage of exons from RNA-seq data , 2012, Genome research.

[33]  D. Hume,et al.  Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. , 2012, Blood.

[34]  Ruth C Lovering,et al.  Transcriptomic analyses of murine resolution-phase macrophages. , 2011, Blood.

[35]  M. Sweet,et al.  Intramacrophage survival of uropathogenic Escherichia coli: differences between diverse clinical isolates and between mouse and human macrophages. , 2011, Immunobiology.

[36]  A. Ferrante,et al.  Regulation of CRIg expression and phagocytosis in human macrophages by arachidonate, dexamethasone, and cytokines. , 2011, The American journal of pathology.

[37]  P. Taylor,et al.  A quantifiable proliferative burst of tissue macrophages restores homeostatic macrophage populations after acute inflammation , 2011, European journal of immunology.

[38]  F. Finkelman,et al.  Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of TH2 Inflammation , 2011, Science.

[39]  L. O’Neill,et al.  MicroRNAs: the fine-tuners of Toll-like receptor signalling , 2011, Nature Reviews Immunology.

[40]  A. Burroughs,et al.  Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. , 2010, Gastroenterology.

[41]  Yuzhang Wu,et al.  Down-regulation of Z39Ig on macrophages by IFN-gamma in patients with chronic HBV infection. , 2010, Clinical immunology.

[42]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[43]  Leonore A. Herzenberg,et al.  Two physically, functionally, and developmentally distinct peritoneal macrophage subsets , 2010, Proceedings of the National Academy of Sciences.

[44]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[45]  R. Schwendener,et al.  Role of CD11b+ macrophages in intraperitoneal lipopolysaccharide-induced aberrant lymphangiogenesis and lymphatic function in the diaphragm. , 2009, The American journal of pathology.

[46]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[47]  M. van Lookeren Campagne,et al.  Complement Receptor of the Ig Superfamily Enhances Complement-Mediated Phagocytosis in a Subpopulation of Tissue Resident Macrophages , 2008, The Journal of Immunology.

[48]  M. van Lookeren Campagne,et al.  A role of macrophage complement receptor CRIg in immune clearance and inflammation. , 2008, Molecular immunology.

[49]  M. van Lookeren Campagne,et al.  A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritis , 2007, The Journal of experimental medicine.

[50]  M. Kurrer,et al.  VSIG4, a B7 family-related protein, is a negative regulator of T cell activation. , 2006, The Journal of clinical investigation.

[51]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[52]  L. Diehl,et al.  CRIg: A Macrophage Complement Receptor Required for Phagocytosis of Circulating Pathogens , 2006, Cell.

[53]  Alexander R. Abbas,et al.  Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data , 2005, Genes and Immunity.

[54]  E. Cholongitas,et al.  Increasing frequency of Gram‐positive bacteria in spontaneous bacterial peritonitis , 2005, Liver international : official journal of the International Association for the Study of the Liver.

[55]  C. Burgaleta,et al.  Effect of granulocyte-macrophage colony-stimulating factor on leukocyte function in cirrhosis. , 1993, Gastroenterology.

[56]  C. Lieber,et al.  Hepatic vitamin A depletion in alcoholic liver injury. , 1982, The New England journal of medicine.

[57]  M. Geuking,et al.  Pathological bacterial translocation in liver cirrhosis. , 2014, Journal of hepatology.

[58]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[59]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[60]  C. Mackenzie,et al.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. , 1987, Journal of chronic diseases.