Extratubular polymerized uromodulin induces leukocyte recruitment and inflammation in vivo

  • Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) in the tubular lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment in vivo and led to TNF-α secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-α. Interestingly, pUMOD displayed no chemotactic properties on neutrophils, did not directly activate β2 integrins and did not upregulate adhesionUromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) in the tubular lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment in vivo and led to TNF-α secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-α. Interestingly, pUMOD displayed no chemotactic properties on neutrophils, did not directly activate β2 integrins and did not upregulate adhesion molecules on endothelial cells. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation in the renal interstitium with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies.show moreshow less

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Author:Roland Immler, Bärbel Lange-Sperandio, Tobias Steffen, Heike Beck, Ina Rohwedder, Jonas Roth, Matteo Napoli, Georg Hupel, Frederik Pfister, Bastian Popper, Bernd Uhl, Hanna MannellGND, Christoph A. Reichel, Volker Vielhauer, Jürgen Scherberich, Markus Sperandio, Monika Pruenster
URN:urn:nbn:de:bvb:384-opus4-1080155
Frontdoor URLhttps://opus.bibliothek.uni-augsburg.de/opus4/108015
ISSN:1664-3224OPAC
Parent Title (English):Frontiers in Immunology
Publisher:Frontiers Media SA
Place of publication:Lausanne
Type:Article
Language:English
Year of first Publication:2020
Publishing Institution:Universität Augsburg
Release Date:2023/09/25
Tag:Immunology; Immunology and Allergy
Volume:11
First Page:588245
DOI:https://doi.org/10.3389/fimmu.2020.588245
Institutes:Medizinische Fakultät
Medizinische Fakultät / Lehrstuhl für Physiologie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):CC-BY 4.0: Creative Commons: Namensnennung (mit Print on Demand)