title: A20 inhibition of STAT1 expression in myeloid cells: a novel endogenous regulatory mechanism preventing development of enthesitis.
abstract: OBJECTIVE
  A20 is an important endogenous regulator of inflammation. Single nucleotide polymorphisms in A20 have been associated with various immune-mediated inflammatory diseases, and cell-specific deletion of A20 results in diverse inflammatory phenotypes. Our goal was to delineate the underlying mechanisms of joint inflammation in myeloid-specific A20-deficient mice (A20myelKOmice).
  
  
  METHODS
  Inflammation in A20myelKOmice was assessed in a time-dependent manner. Western blot analysis and quantitative PCR analysis were performed on bone marrow-derived macrophages from A20myelKOand littermate control mice to study the effect of A20 on STAT1/STAT3 expression and STAT1/STAT3-dependent gene transcription in myeloid cells. The in vivo role of Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling in the development of enthesitis in A20myelKOmice was assessed following administration of a JAK inhibitor versus placebo control.
  
  
  RESULTS
  Enthesitis was found to be an early inflammatory lesion in A20myelKOmice. A20 negatively modulated STAT1-dependent, but generally not STAT3-dependent gene transcription in myeloid cells by suppressing STAT1 but not STAT3 expression, both in unstimulated conditions and after interferon-γ or interleukin-6 stimulation. The increase in STAT1 gene transcription in the absence of A20 was shown to be JAK-STAT-dependent. Moreover, JAK inhibition in vivo resulted in significant reduction of enthesitis, both clinically and histopathologically.
  
  
  CONCLUSIONS
  Our data reveal an important and novel interplay between myeloid cells and tissue resident cells at entheseal sites that is regulated by A20. In the absence of A20, STAT1 but not STAT3 expression is enhanced leading to STAT1-dependent inflammation. Therefore, A20 acts as a novel endogenous regulator of STAT1 that prevents onset of enthesitis.
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.|Department of Rheumatology, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Katelijne
authors.initials: K
authors.lastname: De Wilde
authors.affiliation: Unit of Cellular and Molecular (Patho)physiology, VIB Inflammation Research Center, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Arne
authors.initials: A
authors.lastname: Martens
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.|Department of Rheumatology, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Lambrecht
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.|Department of Rheumatology, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Peggy
authors.initials: P
authors.lastname: Jacques
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.|Department of Rheumatology, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Drennan
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.|Department of Rheumatology, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Karlijn
authors.initials: K
authors.lastname: Debusschere
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.|Department of Rheumatology, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Srinath
authors.initials: S
authors.lastname: Govindarajan
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.|Department of Rheumatology, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Coudenys
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.|Department of Rheumatology, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Eveline
authors.initials: E
authors.lastname: Verheugen
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.|Department of Rheumatology, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Fien
authors.initials: F
authors.lastname: Windels
authors.affiliation: Unit of Cellular and Molecular (Patho)physiology, VIB Inflammation Research Center, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Catrysse
authors.affiliation: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium.|Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Lories
authors.affiliation: The Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
authors.forename: Dennis
authors.initials: D
authors.lastname: McGonagle
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.|Unit of Molecular Signal Transduction in Inflammation, VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Unit of Cellular and Molecular (Patho)physiology, VIB Inflammation Research Center, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.affiliation: Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent, Belgium.|Department of Rheumatology, Department of Internal Medicine, Ghent University, Ghent, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000070676:Enthesopathy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D007371:Interferon-gamma; C479163:tofacitinib; D053612:Janus Kinases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C513261:Tnfaip3 protein, mouse
keywords: Cytokines; Inflammation; Psoriatic Arthritis; Spondyloarthritis