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MIF in kidney diseases

A story of Dr. Jekyll and Mr. Hyde
Lectures Laureates: Rudolf-Virchow-Laureate 2018
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Abstract

Background

Macrophage migration-inhibitory factor (MIF) is a cytokine best known for its proinflammatory and disease-aggravating role in a number of conditions, including atherosclerosis, autoimmune diseases, sepsis, and glomerulonephritides.

Objectives

In our studies we aimed to define the role of MIF on local renal resident cells, in particular the renal epithelium.

Results

We have shown that MIF exerts local effects on glomerular cells, in particular the parietal epithelial cells and mesangial cells, promoting their pathological proliferation and aggravating disease course of a murine model of immune-mediated glomerulonephritis. In contrast, in a large set of animal and in vitro experiments, we have shown that in the setting of chronic kidney disease, MIF had an unexpected and potent antifibrotic and anti-inflammatory effect. This was mediated by enhanced regeneration and reduced cell-cycle arrest of tubular epithelial cells. Finally, in a combined approach using clinical studies, animal models, and in vitro experiments, we have shown that MIF is also renoprotective in the setting of acute kidney injury. In this setting, MIF-modulated programmed cell death of tubular cells and thereby reduced necroinflammation and kidney injury.

Conclusions

Taken together, MIF has a dual role in kidney diseases, promoting (auto)immune glomerular diseases and limiting tubular cell injury in the setting of acute and chronic kidney diseases. These data suggest potential safety issues of systemic MIF targeted therapies, but also open new therapeutic options by targeting MIF or its analogues to tubular cells.

Keywords

Acute kidney injury Chronic renal insufficiency Glomerulonephritis Macrophage migration-inhibitory factors Cell proliferation 

MIF in Nierenerkrankungen

Eine Geschichte über Dr. Jekyll und Mr. Hyde

Zusammenfassung

Hintergrund

„Macrophage migration-inhibitory factor“ (MIF) ist ein Zytokin, das bei einer Vielzahl von Erkrankungen einschließlich Atherosklerose, Autoimmunkrankheiten, Sepsis und Glomerulonephritiden eine proinflammatorische Rolle spielt.

Material und Methoden

In unseren Studien haben wir die Funktion von MIF auf die residenten Nierenzellen, insbesondere die renalen Tubulusepithelien untersucht.

Ergebnisse

Wir konnten zeigen, dass MIF direkte lokale Effekte auf die pathologische Proliferation von glomerulären Zellen ausübt, insbesondere auf die parietalen Epithelzellen und Mesangialzellen, und dadurch den Krankheitsverlauf einer immunvermittelten Glomerulonephritis aggraviert. Im Gegensatz dazu haben wir in einer Reihe von Tier- und In-vitro-Experimenten gezeigt, dass MIF im Rahmen einer chronischen Nierenerkrankung eine unerwartet stark antifibrotische und entzündungshemmende Wirkung hat. Dies ist mechanistisch durch Förderung der Regeneration und Hemmung des Zellzyklusarrestes der tubulären Epithelzellen vermittelt. Schließlich haben wir in einem kombinierten Ansatz unter Verwendung von klinischen Studien und Tiermodellen sowie mittels In-vitro-Experimenten gezeigt, dass MIF auch im Rahmen der akuten Nierenschädigung renoprotektiv wirkt. In diesem Kontext modulierte MIF den programmierten Zelltod und verringerte dadurch die Nekroinflammation und den Nierenschaden.

Schlussfolgerungen

MIF hat eine duale Rolle bei Nierenerkrankungen. Einerseits fördert es immunvermittelte glomeruläre Erkrankungen, andererseits limitiert es tubulären Zellschaden bei akuten und chronischen Nierenerkrankungen. Diese Daten weisen auf mögliche Nebenwirkungen von systemischen MIF-gerichteten Therapien hin, eröffnen aber auch neue Möglichkeiten einer tubuluszellgerichteten Therapie von MIF oder seinen Analoga.

Schlüsselwörter

Akute Nierenschädigung Chronische Niereninsuffizienz Glomerulonephritis „Macrophage migration-inhibitory factors“ Zellteilung 

Notes

Acknowledgements

I am particularly grateful for the excellent and unique commitment and scientific work of Dr. Sonja Djudjaj, who was instrumental in all these projects. I would also like to express a special thanks to my mentors, Prof. Ruth Knüchel-Clarke, Prof. Kerstin Amann, and Prof. Jürgen Floege. My thanks also go to all the present and past members of the LaBooratory of Nephropathology and the many cooperation partners.

Funding

These studies were supported by the German Research Foundation (DFG: SFB/TRR57, SFB/TRR219, BO3755/3-1, and BO 3755/6-1), the German Ministry of Education and Research (BMBF: STOP-FSGS-01GM1518A), the RWTH START program (110/15), and the Interdisciplinary Center for Clinical Research (IZKF, O3-7).

Compliance with ethical guidelines

Conflict of interest

P. Boor declares that he has no competing interests.

This article does not contain any studies with human participants or animals performed by any of the authors.

The supplement containing this article is not sponsored by industry.

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Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Pathology, University ClinicRWTH University of AachenAachenGermany
  2. 2.Division of NephrologyRWTH University of AachenAachenGermany

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