NRF2 promotes urothelial cell response to bacterial infection by regulating reactive oxygen species and RAB27B expression

Joshi, Chetanchandra S.; Mora, Amy; Felder, Paul A.; Mysorekar, Indira U.

doi:10.1016/j.celrep.2021.109856

Cited by 34 publications

(25 citation statements)

References 50 publications

(56 reference statements)

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“…We and others have shown that dysfunctional autophagy leads to downregulation of the antioxidant response (Joshi et al, 2021; Qiao et al, 2020; Yun et al, 2020; Zhao et al, 2019). In agreement with previous findings (de Rijk et al, 2022), we report here that the aged bladder has elevated levels of ROS.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, Nrf2 signaling is known to protect cells from pyroptosis by attenuating the activation of the NLRP3 inflammasome (Kensler et al, 2007). Furthermore, we have demonstrated that Nrf2 -/- mice also exhibit spontaneous urothelial shedding in urine and the shed cells are highly ROS-positive (Joshi et al, 2021). Thus, urothelial shedding in response to unmitigated ROS could represent an inability to repair damaged/stressed cells.…”

Section: Discussionmentioning

confidence: 99%

“…Immune infiltration, along with the inflammatory response, limits further invasion of UPEC. The bladder also activates antioxidant pathways via NRF2 to prevent high ROS build-up in the urothelium (Joshi et al, 2021;Wang et al, 2019), as this balance is essential to avoid excessive cell damage.…”

Section: Introductionmentioning

confidence: 99%

“…Recognition of intracellular bacteria via host TLR-4/NLR receptors triggers the production of reactive oxygen species (ROS) (Joshi et al, 2021) and activates autophagic processes to expel bacteria into the bladder lumen (Terlizzi et al, 2017; thereby restricting further spread of UPEC.…”

Section: Introductionmentioning

confidence: 99%

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D-mannose ameliorates age-associated cellular senescence in the bladder urothelium and NLRP3/Gasdermin/IL-1β -driven pyroptotic epithelial cell shedding

Joshi

Salazar

Wang

et al. 2022

Preprint

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Aging is a risk factor for disease via increased susceptibility to infection, decreased ability to maintain homeostasis, inefficiency in combatting stress, and decreased regenerative capacity. Multiple diseases including urinary tract infection (UTI), are more prevalent with age; however, the mechanisms underlying how aging affects the urinary tract mucosa and the reason why aging correlates with disease are 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 decreased acid phosphatase activity and shows overall decreased autophagic flux. Aged bladders exhibit basally high accumulation of reactive oxygen species (ROS) and dampened redox response. Furthermore, the aged urothelium exhibits a canonical senescence-associated secretory phenotype (SASP) at baseline with continuous NLRP3-inflammasome- and Gasdermin D (GSDMD)-dependent pyroptotic cell death. Accordingly, we find that aged mice chronically exfoliate epithelial cells. When infected with uropathogenic E. coli, infected aged mice harbor more bacterial reservoirs post-infection and are prone to spontaneous recurrent UTI. Finally, treatment of aged mice with D-Mannose, a natural bioactive monosaccharide, rescues autophagy flux, reverses SASP, and limits pyroptotic epithelial shedding. Thus, normal aging dramatically affects bladder physiology with aging alone increasing baseline cellular stress and susceptibility to infection. Additionally, our results suggest that mannose supplementation could serve as a senotherapeutic to limit age-associated urothelial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

D-mannose ameliorates age-associated cellular senescence in the bladder urothelium and NLRP3/Gasdermin/IL-1β -driven pyroptotic epithelial cell shedding

Joshi

Salazar

Wang

et al. 2022

Preprint

Self Cite

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“…In a study comparing various Nrf2 activators, sulforaphane was shown to have the greatest effect on decreasing inflammation and improving macrophage bacterial clearance ( 17 ). Furthermore, dimethyl fumarate, another Nrf2 signaling activator, was shown to promote clearance of uropathogenic E. coli in a mouse model of urinary tract infection (UTI) ( 21 ). UTIs are often recalcitrant to antibiotic treatment, underpinning the utility of host-directed therapeutics against bacterial infections.…”

Section: Discussionmentioning

confidence: 99%

The Use of Acute Immunosuppressive Therapy to Improve Antibiotic Efficacy against Intracellular Staphylococcus aureus

et al. 2022

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Tolterodine ameliorates inflammatory response and ferroptosis against LPS in human bladder epithelial cells

Wang,

Ji,

Jiang

et al. 2023

J Biochem & Molecular Tox

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Bacterial endotoxin lipopolysaccharide (LPS)‐induced inflammatory response and ferroptosis play an important role in urinary tract infections. Tolterodine has been used as a urinary tract antispasmodic and anticholinergic agent. However, the effects of Tolterodine against LPS‐induced insults in human bladder epithelial cells (hBECs) have not been reported before. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide and lactate dehydrogenase release assays to determine the cell viability, reactive oxygen species (ROS) and malondialdehyde level detection were used to determine the level of oxidative stress, enzyme‐linked immunosorbent assay and Western blot analysis were used to detect the protein level. In the current study, we found that Tolterodine ameliorated LPS‐induced production of ROS and lipid oxidation in hBECs. Interestingly, Tolterodine inhibited the production of interleukin 6, interleukin‐1β, and tumor necrosis factor α. Also, Tolterodine reduced the levels of Fe2+ and suppressed ferroptosis by reducing the levels of glutathione peroxidase 4, prostaglandin‐endoperoxide synthase 2, and acyl‐CoA synthetase long‐chain family member 4 in LPS‐challenged bladder epithelial cells. Mechanistically, it was shown that Tolterodine restored the nuclear factor E2‐related factor 2 (Nrf2)/nuclear factor‐κB signaling. Importantly, inhibition of Nrf2 with its specific inhibitor ML385 abolished the protective effects of Tolterodine in the inflammatory response and ferroptosis, suggesting that the effects of Tolterodine are mediated by Nrf2. Based on these findings, we conclude that Tolterodine might serve as a promising agent for the treatment of LPS‐induced bladder inflammation.

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NRF2 promotes urothelial cell response to bacterial infection by regulating reactive oxygen species and RAB27B expression

Cited by 34 publications

References 50 publications

D-mannose ameliorates age-associated cellular senescence in the bladder urothelium and NLRP3/Gasdermin/IL-1β -driven pyroptotic epithelial cell shedding

D-mannose ameliorates age-associated cellular senescence in the bladder urothelium and NLRP3/Gasdermin/IL-1β -driven pyroptotic epithelial cell shedding

The Use of Acute Immunosuppressive Therapy to Improve Antibiotic Efficacy against Intracellular Staphylococcus aureus

Tolterodine ameliorates inflammatory response and ferroptosis against LPS in human bladder epithelial cells

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