Language

English

Publication Date

1-9-2025

Journal

JCI Insight

DOI

10.1172/jci.insight.180024

PMID

39589812

PMCID

PMC11721310

PubMedCentral® Posted Date

1-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Urinary neutrophils are a hallmark of urinary tract infection (UTI), yet the mechanisms governing their activation, function, and efficacy in controlling infection remain incompletely understood. Tamm-Horsfall glycoprotein (THP), the most abundant protein in urine, uses terminal sialic acids to bind an inhibitory receptor and dampen neutrophil inflammatory responses. We hypothesized that neutrophil modulation is an integral part of THP-mediated host protection. In a UTI model, THP-deficient mice showed elevated urinary tract bacterial burdens, increased neutrophil recruitment, and more severe tissue histopathological changes compared with WT mice. Furthermore, THP-deficient mice displayed impaired urinary NETosis during UTI. To investigate the effect of THP on NETosis, we coupled in vitro fluorescence-based NET assays, proteomic analyses, and standard and imaging flow cytometry with peripheral human neutrophils. We found that THP increases proteins involved in respiratory chain, neutrophil granules, and chromatin remodeling pathways; enhances NETosis in an ROS-dependent manner; and drives NET-associated morphologic features including nuclear decondensation. These effects were observed only in the presence of a NETosis stimulus and could not be solely replicated with equivalent levels of sialic acid alone. We conclude that THP is a critical regulator of NETosis in the urinary tract, playing a key role in host defense against UTI.

Keywords

Uromodulin, Urinary Tract Infections, Animals, Neutrophils, Mice, Humans, Extracellular Traps, Female, Disease Models, Animal, Mice, Knockout, Mice, Inbred C57BL, Immunology, Infectious disease, Mouse models, Neutrophils, UTI/pyelonephritis

Published Open-Access

yes

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