Extratubular polymerized uromodulin induces leukocyte recruitment and inflammationin vivo

Abstract

Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) within the 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 did not directly upregulate adhesion molecules on endothelial cells and did not directly activate β2 integrins on neutrophils. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation 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.

The Effect of miR-505-5p on Inhibition of Serum Uromodulin Ameliorates Myocardial Inflammation and Apoptosis Induced by Ischemia-Reperfusion

“…sUmod was reported to interact with myoloid dendritic cells (DCs), monocytes, and neutrophils through toll-like receptor 4 (TLR4), and has an effect on the regulation of inflammation as well as innate immunity [30], and the immunosuppressive effect of sUmod was achieved by binding to TNF-α and interleukin-1 [31]. In addition, sUmod stimulated extrarenal tissue, and caused strong inflammatory response, which was characterized by obviously recruiting inflammatory monocytes and neutrophils [32]. sUmod induced the secretion of TNF-α and the expression of tissue factors in human monocytes, triggered DC maturation through activating NF-κB and TLR4, and activated protease release, respiratory burst, degranulation, and phagocytosis of neutrophils [33].…”

Extratubular Polymerized Uromodulin Induces Leukocyte Recruitment and Inflammation In Vivo

“…In addition, we thank Susanne Bierschenk, Nadine Schmidt, Dorothee Gössel, and Ursula Keller for excellent technical assistance as well as the core facility BioImaging at the Biomedical Center, LMU Planegg-Martinsried, Germany for their help with microscopy. This manuscript has been released as a pre-print at bioRxiv ( 64 ).…”