D-mannose Reduces Cellular Senescence and NLRP3/GasderminD/Il-1β-Driven Pyroptotic Uroepithelial Cell Shedding in the Murine Bladder

Authors

Chetanchandra S Joshi
Arnold M Salazar
Caihong Wang
Marianne M Ligon
Rayvanth R Chappidi
Bisiayo E Fashemi
Paul A Felder
Amy Mora
Sandra L Grimm
Cristian Coarfa
Indira U Mysorekar

Publication Date

1-8-2024

Journal

Developmental Cell

DOI

10.1016/j.devcel.2023.11.017

PMID

38101412

PMCID

PMC10872954

PubMedCentral® Posted Date

1-8-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Mice, Female, Animals, NLR Family, Pyrin Domain-Containing 3 Protein, Urinary Bladder, Mannose, Reactive Oxygen Species, Escherichia coli, Urothelium, Interleukin-1beta, Gasdermins, Urinary Tract Infections, Cellular Senescence

Abstract

Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combating stress, and decreased regenerative capacity. Multiple diseases, including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying the impact of aging on the urinary tract mucosa and the correlation between aging and disease remain poorly understood. Here, we show that, relative to young (8-12 weeks) mice, the urothelium of aged (18-24 months) female mice accumulates large lysosomes with reduced acid phosphatase activity and decreased overall autophagic flux in the aged urothelium, indicative of compromised cellular homeostasis. Aged bladders also exhibit basal accumulation of reactive oxygen species (ROS) and a dampened redox response, implying heightened oxidative stress. Furthermore, we identify a canonical senescence-associated secretory phenotype (SASP) in the aged urothelium, along with continuous NLRP3-inflammasome- and Gasdermin-D-dependent pyroptotic cell death. Consequently, aged mice chronically exfoliate urothelial cells, further exacerbating age-related urothelial dysfunction. Upon infection with uropathogenic E. coli, aged mice harbor increased bacterial reservoirs and are more prone to spontaneous recurrent UTI. Finally, we discover that treatment with D-mannose, a natural bioactive monosaccharide, rescues autophagy flux, reverses the SASP, and mitigates ROS and NLRP3/Gasdermin/interleukin (IL)-1β-driven pyroptotic epithelial cell shedding in aged mice. Collectively, our results demonstrate that normal aging affects bladder physiology, with aging alone increasing baseline cellular stress and susceptibility to infection, and suggest that mannose supplementation could serve as a senotherapeutic to counter age-associated urothelial dysfunction.

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