The NLRP3 Inflammasome Mediates Inflammation Produced by Bladder Outlet Obstruction

Abstract

Purpose While bladder outlet obstruction (BOO) is well-established to elicit an inflammatory reaction in the bladder that leads to overactive bladder and fibrosis, little is known about the mechanism by which this is initiated. Nod-Like Receptors (NLRs) and the structures they form (inflammasomes) have been identified as sensors of cellular damage (including pressure-induced damage) and triggers of inflammation. Recently, we identified these structures in the urothelium. In this study we assess the role of the NLRP3 inflammasome in the bladder dysfunction resulting from BOO. Materials and Methods BOO was created in female rats by insertion of a 1 mm (o.d.) transurethral catheter, tying a silk ligature around the urethra and removing the catheter. Untreated and sham-operated rats served as controls. BOO rats were given vehicle (10% ethanol) or 10 mg/kg of glyburide (an NLRP3 inhibitor; daily for 12 days, p.o.). Inflammasome activity, bladder hypertrophy, inflammation and bladder function (urodynamics) were assessed. Results: BOO increased urothelial inflammasome activity, bladder hypertrophy, and inflammation and reduced voiding volume. Glyburide blocked inflammasome activation, reduced hypertrophy and prevented inflammation. The reduction in void volume was also attenuated by glyburide, mechanistically by an increase in the duration of detrusor contraction and voiding period. Conclusion The results suggest the importance of the NLRP3 inflammasome in the induction of inflammation and bladder dysfunction secondary to BOO. Arresting these processes with NLRP3 inhibitors may prove useful in treating the symptoms they produce.

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

“…IL‐1β and IL‐18 are pro‐inflammatory cytokines which trigger the inflammatory response. We have shown in rats that an inhibitor of NLRP3, glyburide, not only blocks BOO‐induced inflammation but also the irritative voiding symptoms and downstream fibrosis . In this study, we explore a role for NLRP3‐mediated inflammation in triggering the denervation of the bladder that occurs following BOO .…”

“…However, over time symptoms progress toward bladder overactivity (increased frequency and urgency) and urge incontinence, defined as an irritative voiding pattern . Previous studies suggested that bladder inflammation underlies these irritative voiding symptoms . Although symptomatic relief is often possible with medications (alpha blockers, 5‐alpha reductase inhibitors, antimuscarinics, and β3‐agonists), these treatments do not fully alleviate the outflow resistance and the repeated physical/chemical insults associated with it.…”

“…While the mechanism of denervation remains unknown, it has been speculated to result from hypoxia and reperfusion with production of reactive oxygen species (ROS) . ROS can be an activator of the NLRP3 inflammasome and our lab has been exploring the importance of NLRP3 to the underlying inflammation and pathological changes in the bladder during BOO . NLRP3 is a member of the NOD‐like family of intracellular receptors.…”

New Frontiers in Molecular and Imaging Research on Evaluation and Diagnosis of Bladder Outlet Obstruction in Women

“…In a rat model of BOO, administration of a NLRP3 inhibitor (glyburide) was shown to block inflammasome activation, reduce hypertrophy, and prevent inflammation (54). This may represent a pathway that can be targeted with treatment of symptoms induced by BOO, related to the inflammatory response and development of OAB symptoms.…”

The NACHT, LRR and PYD Domains-Containing protein 3 (NLRP3) Inflammasome Mediates Inflammation and Voiding Dysfunction in a Lipopolysaccharide-Induced Rat Model of Cystitis

“…NLRP3 is by far the best studied inflammasome and has been shown to respond to numerous DAMPs as well as PAMPs. Our lab has recently documented the presence of this NLR/ inflammasome (and several others) in the bladder urothelia [8] and its central role in two critical models of sterile inflammation (cyclophosphamide-induced hemmoragic cystitis and bladder outlet obstruction) [9,10]. Among the list of PAMPS that activate this inflammasome (directly or indirectly), lipopolysaccharide (LPS) is one of the most potent virulence factors of uropathogens [11].…”