Uromodulin Facilitates Neutrophil Migration Across Renal Epithelial Monolayers

Abstract

The glycosylated protein uromodulin is exclusively found in the thick ascending limb cells (TAL) of the kidney, where it is produced on mass and apically targeted, eventually being secreted into the urine. Recently, there has been a renewed interest in this protein due to its ability to interact with the immune system, implicating this protein as a renal inflammatory molecule. Here we investigated the potential role of membrane bound uromodulin on neutrophil adhesion and trans-epithelial migration. The renal tubular epithelial cell line, LLC-PK1, stably transfected with human uromodulin was used to investigate the influence of uromodulin on neutrophil adherence and migration. Uromodulin expression resulted in a significant increase of neutrophil adherence and trans-epithelial migration, in both the apical to basolateral and the basolateral to apical direction. Although uromodulin is GPI anchored and targeted to the apical membrane, we could also observe expression in the basal and lateral membranes domains, which may be responsible for basolateral to apical migration. Furthermore we show that uromodulin binds both the heavy and light chain of IgG, and that IgG enhances neutrophil migration. This study demonstrates that uromodulin can facilitate neutrophil trans-epithelial migration and that this migration can be amplified by co-factors such as IgG.

Identification of Pancreatic Glycoprotein 2 as an Endogenous Immunomodulator of Innate and Adaptive Immune Responses

“…THP was reported to influence chemotaxis of polymorphonuclear leukocytes (45), as well as neutrophils (36), and it fosters bacterial phagocytosis (46,47). In this study we provide clear evidence that THP and GP2 share functional and immunological resemblances.…”

“…THP, the renal homolog of GP2, was recently reported to increase transepithelial migration of neutrophils (36). We show that GP2 increased mononuclear cell migration toward GP2-treated epithelial cells.…”

Detection of Renal Tissue and Urinary Tract Proteins in the Human Urine after Space Flight

“…Uromodulin is glycosylphosphatidylinositol-anchored protein. Uromodulin expression resulted in a significant increase of neutrophil adhesion (after binding the heavy and light chains of IgG) and trans-epithelial migration, in both the apical-to-basolateral and the basolateral-to-apical directions [16].…”

The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution

“…56 At physiologic concentrations, uromodulin abolishes the binding of E. coli to uroplakin receptors and, through its interactions with host factors like IgG heavy and light chains, facilitates neutrophil migration. 57,58 Conversely, uropathogenic E. coli were more abundant, caused more severe renal infections and acute mortality, and persisted longer in uromodulin knockout mice. 5 Our data, showing for the first time an inverse correlation of urinary uromodulin levels and local and systemic markers of UTIs, support the view that higher levels of uromodulin in the urine, determined by the presence of the UMOD ancestral allele, 50 exert a protective effect against UTIs in the general population.…”