title: Podocytes regulate neutrophil recruitment by glomerular endothelial cells via IL-6-mediated crosstalk.
abstract: Stromal cells actively modulate the inflammatory process, in part by influencing the ability of neighboring endothelial cells to support the recruitment of circulating leukocytes. We hypothesized that podocytes influence the ability of glomerular endothelial cells (GEnCs) to recruit neutrophils during inflammation. To address this, human podocytes and human GEnCs were cultured on opposite sides of porous inserts and then treated with or without increasing concentrations of TNF-α prior to addition of neutrophils. The presence of podocytes significantly reduced neutrophil recruitment to GEnCs by up to 50% when cultures were treated with high-dose TNF-α (100 U/ml), when compared with GEnC monocultures. Importantly, this phenomenon was dependent on paracrine actions of soluble IL-6, predominantly released by podocytes. A similar response was absent when HUVECs were cocultured with podocytes, indicating a tissue-specific phenomenon. Suppressor of cytokine signaling 3 elicited the immunosuppressive actions of IL-6 in a process that disrupted the presentation of chemokines on GEnCs by altering the expression of the duffy Ag receptor for chemokines. Interestingly, suppressor of cytokine signaling 3 knockdown in GEnCs upregulated duffy Ag receptor for chemokines and CXCL5 expression, thereby restoring the neutrophil recruitment. In summary, these studies reveal that podocytes can negatively regulate neutrophil recruitment to inflamed GEnCs by modulating IL-6 signaling, identifying a potential novel anti-inflammatory role of IL-6 in renal glomeruli.
authors.affiliation: Centre for Translational Inflammation Research, School of Immunity and Infection, University of Birmingham, Birmingham B15 2TT, United Kingdom; s.j.panchagnula@bham.ac.uk.
authors.forename: Sahithi J
authors.initials: SJ
authors.lastname: Kuravi
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGettrick
authors.affiliation: Academic Renal Unit, Southmead Hospital, Bristol BS10 5NB, United Kingdom;
authors.forename: Simon C
authors.initials: SC
authors.lastname: Satchell
authors.affiliation: Academic Renal Unit, Southmead Hospital, Bristol BS10 5NB, United Kingdom;
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Centre for Translational Inflammation Research, School of Immunity and Infection, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Lorraine
authors.initials: L
authors.lastname: Harper
authors.affiliation: Wellcome Trust Clinical Research Facility, University Hospital Birmingham Foundation Trust, Birmingham B15 2TH, United Kingdom; and.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Williams
authors.affiliation: Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: George Ed
authors.initials: GE
authors.lastname: Rainger
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Caroline O S
authors.initials: CO
authors.lastname: Savage
mesh_terms: D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D002461:Cell Line, Transformed; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008297:Male; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D050199:Podocytes / Q000166:cytology / Q000276:immunology*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000276:immunology
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C527785:SOX3 protein, human; D055748:SOXB1 Transcription Factors