NLRP3/IL1β inflammasome associated with the aging bladder triggers bladder dysfunction in female rats

Abstract

Bladder dysfunction is associated with fibrosis-mediated aging, but the corresponding mechanism remains to be elucidated. Activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is related to chronic diseases associated with aging, including organ fibrosis. The present study aimed to explore the role of NLRP3/interleukin 1β in aging-associated bladder dysfunction. Female Sprague-Dawley rats were divided into the following two groups (n=10 rats/group): 2-month-old group (young group) and 24-month-old group (old group). Urodynamics were performed to assess the bladder function of the rats. The histological alterations were identified using Masson's trichrome staining. The protein expression of the NLRP3 inflammasome and NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3) were detected by western blot analysis, and immunohistochemistry was used to examine a senescence marker (p21) and the NLRP3 inflammasome in the bladder. The localization of the key molecule Caspase1 was determined using immunofluorescence. The voiding time was longer in the old group compared with the young group. The expression levels of SIRT3 were reduced in the bladders of the old group, while those of the NLRP3 inflammasome and the senescence marker were significantly higher in the bladders of the old group compared with the young group. Increased collagen deposition leads to chronic bladder fibrosis with increased NLRP3. In the histological examination, the bladders of the old group displayed increased collagen deposition, urothelial thinning and detrusor shrinkage compared with the young group. Tissue fibrosis and urothelial alterations are the principal causes of bladder dysfunction during aging. Downregulated SIRT3 and upregulated expression of the NLRP3 inflammasome are involved in the degradation of aging bladders. Inflamm-aging is a novel mechanism underlying bladder dysfunction.

Cellular senescence induced by S100A9 in mesenchymal stromal cells through NLRP3 inflammasome activation

“…IL-1β plays an important role in the interaction between tumor cells and their bone marrow microenvironment [44]. IL-1β produced by NLRP3 inflammasomes is a key molecule in cell senescence [45–48]. In our study, IL-1β induced cellular senescence in HS-27a and primary MSC cells, and IL-1β knockdown decreased cellular senescence induced by S100A9.…”

Specialized pro-resolution mediators in the bladder: Receptor expression and recovery of bladder function from cystitis

“…Recently, our laboratory and others have shown a critical role for the NLRP3 inflammasome in acute stimuli such as chemotherapeutic cystitis 21 (caused by cyclophosphamide [CP] which is the model employed in this study) and urinary tract infections [5][6][7] as well as in the more chronic inflammatory bladder diseases such as BOO, 1 diabetic bladder dysfunction, 4 interstitial cystitis/chronic bladder pain syndrome, 8 and aging. 9 In these studies, pharmacological inhibitors or genetic deletion of NLRP3 showed the utility of targeting this complex in preventing bladder inflammation and the negative consequences of these conditions. However, there are two major problems with this approach that makes it less desirable in all circumstances.…”

“…Despite this, CP-induced cystitis remains a very useful experimental model for bladder inflammation because of its speed and reproducibility and important findings with this model are often confirmed and expanded upon in more chronic and clinically relevant models. For example, studies of NLRP3 in CP-induced cystitis 21 led to an understanding of its role in BOO, 1 diabetes, 4 urinary tract infections, [5][6][7] interstitial cystitis/ chronic bladder pain syndrome, 8 aging, 9 and even mood disorders associated with lower urinary tract symptoms. 36 Injection of 150 mg/kg CP elicits advanced inflammatory characteristics in the bladder within 24 h and this inflammation persists for >one week.…”

“…Bladder inflammation is a precipitating or exacerbating factor in many benign urological diseases including bladder outlet obstruction (BOO), 1 diabetic bladder dysfunction, 2–4 urinary tract infections, 5–7 interstitial cystitis/bladder pain syndrome, 8 and even aging. 9 Thus, understanding the common underlying pathways that control inflammation in the bladder should identify molecular targets that could be modulated to reduce the severity and/or morbidity of many, if not all, of the diverse bladder inflammatory disorders.…”

Zapalenie starcze - mechanizmy i szlaki sygnałowe

“…W pęcherzu moczowym starych (24-miesięcznych) szczurów obserwowano zmniejszoną ekspresję białka Sirt3 oraz wzrost aktywacji inflamasomu NLRP3, w porównaniu do młodych (2-miesięcznych) szczurów. Powyższe zmiany przyczyniają się do starzenia się komórek wskazując, że zapalenie starcze jest mechanizmem prowadzącym do dysfunkcji pęcherza moczowego [38]. W mózgu wyizolowanym z młodych (3 miesięcznych) i starych (18-miesięcznych) myszy zaobserwowano związaną z wiekiem zwiększoną aktywację inflamasomu NLRC4 (ang.…”