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Control of neutrophil influx during peritonitis by transcriptional cross-regulation of chemokine CXCL1 by IL‐17 and IFN‐γ

Catar, Rusan A., Chen, Lei, Cuff, Simone M., Kift-Morgan, Ann, Eberl, Matthias, Kettritz, Ralph, Kamhieh-Milz, Julian, Moll, Guido, Li, Qing, Zhao, Hongfan, Kawka, Edyta, Zickler, Daniel, Parekh, Gita, Davis, Paul, Fraser, Donald J., Dragun, Duska, Eckardt, Kai-Uwe, Jörres, Achim and Witowski, Janusz 2020. Control of neutrophil influx during peritonitis by transcriptional cross-regulation of chemokine CXCL1 by IL‐17 and IFN‐γ. Journal of Pathology 251 (2) , pp. 175-186. 10.1002/path.5438
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Abstract

Neutrophil infiltration is a hallmark of peritoneal inflammation, but mechanisms regulating neutrophil recruitment in patients with peritoneal dialysis (PD)‐related peritonitis are not fully defined. We examined 104 samples of PD effluent collected during acute peritonitis for correspondence between a broad range of soluble parameters and neutrophil counts. We observed an association between peritoneal IL‐17 and neutrophil levels. This relationship was evident in effluent samples with low but not high IFN‐γ levels, suggesting a differential effect of IFN‐γ concentration on neutrophil infiltration. Surprisingly, there was no association of neutrophil numbers with the level of CXCL1, a key IL‐17‐induced neutrophil chemoattractant. We investigated therefore the production of CXCL1 by human peritoneal mesothelial cells (HPMCs) under in vitro conditions mimicking clinical peritonitis. Stimulation of HPMCs with IL‐17 increased CXCL1 production through induction of transcription factor SP1 and activation of the SP1‐binding region of the CXCL1 promoter. These effects were amplified by TNFα. In contrast, IFN‐γ dose‐dependently suppressed IL‐17‐induced SP1 activation and CXCL1 production through a transcriptional mechanism involving STAT1. The SP1‐mediated induction of CXCL1 was also observed in HPMCs exposed to PD effluent collected during peritonitis and containing IL‐17 and TNFα, but not IFN‐γ. Supplementation of the effluent with IFN‐γ led to a dose‐dependent activation of STAT1 and a resultant inhibition of SP1‐induced CXCL1 expression. Transmesothelial migration of neutrophils in vitro increased upon stimulation of HPMCs with IL‐17 and was reduced by IFN‐γ. In addition, HPMCs were capable of binding CXCL1 at their apical cell surface. These observations indicate that changes in relative peritoneal concentrations of IL‐17 and IFN‐γ can differently engage SP1‐STAT1, impacting on mesothelial cell transcription of CXCL1, whose release and binding to HPMC surface may determine optimal neutrophil recruitment and retention during peritonitis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Wiley
ISSN: 0022-3417
Date of First Compliant Deposit: 1 April 2020
Date of Acceptance: 23 March 2020
Last Modified: 24 Nov 2020 22:57
URI: http://orca-mwe.cf.ac.uk/id/eprint/130666

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