NLRP3/IL‐1β mediates denervation during bladder outlet obstruction in rats

Lütolf, Robin; Hughes, Francis M.; Inouye, Brian M.; Jin, Huixia; McMains, Jennifer; Pak, Elena S.; Hannan, Johanna L.; Purves, J. Todd

doi:10.1002/nau.23419

Cited by 17 publications

(34 citation statements)

References 25 publications

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“…Arrows indicate positive staining, whereas the block arrow indicates nonspecific, or at least nonneuronal, staining of the urothelia. Although the significance of the urothelial staining is unknown, it has been previously reported (27,37). Quantitatively, the total number of nerves in the bladder wall was decreased in the diabetic mouse (Fig.…”

Section: Nlrp3 Controls Changes In the Densities Of Nerves Related Tomentioning

confidence: 69%

“…The signal emanating from the urothelium to trigger effects in the other bladder tissues remains unidentified but likely attributable to the major products of the inflammasome, IL-1b and IL-18, acting in a paracrine fashion. Indeed, we have shown that IL-1b is responsible for the decrease in PGP9.5 + nerves in the bladder wall in a rat model of bladder outlet obstruction (27), whereas others have implicated it in bladder smooth muscle hypertrophy (46).…”

Section: Discussionmentioning

confidence: 93%

“…Quantitation of PGP9.5 and Ad-nerve density in the bladder wall was carried out exactly as previously described (27), whereas quantitation of C-fibers in the urothelium required only minor modifications. Briefly, TIFF files were imported into NIS-Elements software (Nikon Co., Tokyo, Japan), calibrated, the bladder wall or urothelia layer demarcated (the region of interest), and area calculated.…”

Section: Analysis Of Nerve Densitiesmentioning

confidence: 99%

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NLRP3 Promotes Diabetic Bladder Dysfunction and Changes in Symptom-Specific Bladder Innervation

et al. 2018

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The NLRP3 inflammasome senses diabetic metabolites and initiates inflammation implicated in diabetic complications and neurodegeneration. No studies have investigated NLRP3 in diabetic bladder dysfunction (DBD), despite a high clinical prevalence. In vitro, we found that numerous diabetic metabolites activate NLRP3 in primary urothelial cells. In vivo, we demonstrate NLRP3 is activated in urothelia from a genetic type 1 diabetic mouse (Akita) by week 15. We then bred an NLRP3 2/2 genotype into these mice and found this blocked bladder inflammation and cystometric markers of DBD. Analysis of bladder innervation established an NLRP3-dependent decrease in overall nerve density and Ad-fibers in the bladder wall along with an increase in C-fiber populations in the urothelia, which potentially explains the decreased sense of bladder fullness reported by patients and overactivity detected early in DBD. Together, the results demonstrate the role of NLRP3 in the genesis of DBD and suggest specific NLRP3-mediated neuronal changes can produce specific DBD symptoms.

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Section: Nlrp3 Controls Changes In the Densities Of Nerves Related Tomentioning

confidence: 69%

Section: Discussionmentioning

confidence: 93%

Section: Analysis Of Nerve Densitiesmentioning

confidence: 99%

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NLRP3 Promotes Diabetic Bladder Dysfunction and Changes in Symptom-Specific Bladder Innervation

et al. 2018

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“…NLRP3 is widely studied and plays a key role in innate immune‐related sensing among these inflammasomes 8 . The NLRP3 inflammasome has been reported to play an important role in inflammation‐associated bladder diseases 9–12 . However, whether pyroptosis is associated with bladder urothelial cell death upon cigarette smoke exposure and their relationship with bladder disease remains to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Cigarette smoke induces the pyroptosis of urothelial cells through ROS/NLRP3/caspase‐1 signaling pathway

Liu

Zhu

et al. 2020

Neurourology and Urodynamics

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Aims: Cell death and inflammation are involved in the development of bladder dysfunction. Pyroptosis is programmed cell death, causing cytotoxic effects and local inflammation. As one of the biggest health threats in the world, smoking is also closely related to urinary system diseases. The aims of this study were to investigate the role of NLRP3 inflammasome-mediated pyroptosis in the bladder after cigarette smoke exposure. Methods: The expression of NLRP3 inflammasome and the activity of caspase-1 in bladder tissue was investigated after cigarette smoke exposure. In vitro, bladder urothelial cells were stimulated by cigarette smoke extract and then the activity of caspase-1 and the expression of NLRP3 inflammasome were measured. The role of oxidative stress was also assessed.

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“…In particular, localized inflammatory insults in peripheral organs may induce inflammation in the central nervous system (CNS), which triggers clinical depression. 8 Since BOO triggers a chronic inflammatory response in the bladder, [9][10][11] we propose the exploratory hypothesis that it will also elicit inflammation in the CNS that will precipitate mood disorders. Interestingly, Johnson et al 12 first proposed inflammation as the central commonality between LUTS and mood disorders in 2010.…”

Section: Introductionmentioning

confidence: 99%

A possible mechanism underlying mood disorders associated with LUTS: Chronic bladder outlet obstruction causes NLRP3‐dependent inflammation in the hippocampus and depressive behavior in rats

Hughes

Hirshman

Malick

et al. 2020

Neurourology and Urodynamics

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Aims Reports link urinary dysfunction and mood disorders, such as depression, but a causative mechanism has never been postulated. Contemporary discoveries demonstrate a local inflammatory response in peripheral organs can trigger inflammation in the brain, particularly the hippocampus, mediated through the NLRP3 inflammasome. Critically, central inflammation causes depressive behavior. Since bladder outlet obstruction (BOO) evokes a local inflammatory response in the bladder, we hypothesize it will induce NLRP3‐dependent inflammation in the hippocampus and depressive behavior. Methods There were four groups of rats: control, sham, BOO, or BOO + glyburide (an NLRP3 inhibitor). BOO was created by urethral ligation over a 1 mm catheter. Sham was tied loosely. Glyburide was provided by slow‐release pellet (subcutaneous 50 mg, 21 day, replaced as needed). Rats were analyzed 12 weeks post‐op for: hippocampal inflammation, microglial density, neurogenesis, and depression symptoms (open field and sucrose preference). Results BOO elicited hippocampal inflammation, accompanied by an increase in activated microglia (22%) and a decrease in neurogenesis (35%), which was blocked by glyburide. In addition, BOO rats displayed anxiety (57% decrease in exploratory behavior in the open field assay) and anhedonia (21% decrease in sucrose preference), two symptoms of depression. Like inflammation, these symptoms were diminished by glyburide to levels not statistically significantly different from controls. Conclusions BOO, a bladder‐localized event, stimulates NLRP3‐dependent inflammation in the rat hippocampus after 12 weeks and this inflammation causes depressive behavior. This is the first mechanistic explanation of the link between BOO and depression and provides evidence for a distinct bladder‐brain axis.

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NLRP3/IL‐1β mediates denervation during bladder outlet obstruction in rats

Abstract: The NLRP3/IL-1β-mediated inflammation pathway plays a significant role in denervation during BOO.

Cited by 17 publications

References 25 publications

NLRP3 Promotes Diabetic Bladder Dysfunction and Changes in Symptom-Specific Bladder Innervation

NLRP3 Promotes Diabetic Bladder Dysfunction and Changes in Symptom-Specific Bladder Innervation

Cigarette smoke induces the pyroptosis of urothelial cells through ROS/NLRP3/caspase‐1 signaling pathway

A possible mechanism underlying mood disorders associated with LUTS: Chronic bladder outlet obstruction causes NLRP3‐dependent inflammation in the hippocampus and depressive behavior in rats

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