Browsing by Subject "Inflammasomes"

Now showing 1 - 7 of 7
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    Bladder fibrosis during outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1β.
    (American journal of physiology. Renal physiology, 2017-09) Hughes, Francis M; Sexton, Stephanie J; Jin, Huixia; Govada, Vihasa; Purves, J Todd
    Bladder outlet obstruction (BOO) triggers inflammation in the bladder through the NLRP3 inflammasome. BOO also activates fibrosis, which is largely responsible for the decompensation of the bladder in the chronic state. Because fibrosis can be driven by inflammation, we have explored a role for NLRP3 (and IL-1β produced by NLRP3) in the activation and progression of BOO-induced fibrosis. Female rats were divided into five groups: 1) control, 2) sham, 3) BOO + vehicle, 4) BOO + the NLRP3 inhibitor glyburide, or 5) BOO + the IL-1β receptor antagonist anakinra. Fibrosis was assessed by Masson's trichrome stain, collagen secretion via Sirius Red, and protein localization by immunofluorescence. BOO increased collagen production in the bladder, which was blocked by glyburide and anakinra, clearly implicating the NLRP3/IL-1β pathway in fibrosis. The collagen was primarily found in the lamina propria and the smooth muscle, while IL-1 receptor 1 and prolyl 4-hydroylase (an enzyme involved in the intracellular modification of collagen) both localized to the urothelium and the smooth muscle. Lysyl oxidase, the enzyme involved in the final extracellular assembly of mature collagen fibrils, was found to some extent in the lamina propria where its expression was greatly enhanced during BOO. In vitro studies demonstrated isolated urothelial cells from BOO rats secreted substantially more collagen than controls, and collagen expression in control cultures could be directly stimulated by IL-1β. In summary, NLRP3-derived-IL-1β triggers fibrosis during BOO, most likely through an autocrine loop in which IL-1β acts on urothelia to drive collagen production.
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    Inflammasomes in the urinary tract: a disease-based review.
    (American journal of physiology. Renal physiology, 2016-10) Purves, J Todd; Hughes, F Monty
    Inflammasomes are supramolecular structures that sense molecular patterns from pathogenic organisms or damaged cells and trigger an innate immune response, most commonly through production of the proinflammatory cytokines IL-1β and IL-18, but also through less understood mechanisms independent of these cytokines. Great strides have been made in understanding these structures and their dysfunction in various inflammatory diseases, lending new insights into urological and renal problems. From a clinical perspective, benign urinary pathology almost universally involves the inflammatory process, and understanding how inflammasomes translate etiological conditions (diabetes, obstruction, stones, urinary tract infections, etc.) into acute and chronic inflammatory responses is critical to understanding these diseases at a molecular level. To date, inflammasome components have been found in the bladder, prostate, and kidney and have been shown to be activated in response to several infectious and noninfectious insults. In this review, we summarize what is known regarding inflammasomes in both the upper and lower urinary tract and describe several common disease states where they potentially play critical roles.
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    Mitochondrial Quality Control as a Therapeutic Target.
    (Pharmacol Rev, 2016-01) Suliman, Hagir B; Piantadosi, Claude A
    In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control.
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    Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation.
    (Cell reports, 2023-01) Meyers, Allison K; Wang, Zhan; Han, Wenzheng; Zhao, Qingxia; Zabalawi, Manal; Duan, Likun; Liu, Juan; Zhang, Qianyi; Manne, Rajesh K; Lorenzo, Felipe; Quinn, Matthew A; Song, Qianqian; Fan, Daping; Lin, Hui-Kuan; Furdui, Cristina M; Locasale, Jason W; McCall, Charles E; Zhu, Xuewei
    Activating the macrophage NLRP3 inflammasome can promote excessive inflammation with severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages and septic mice by lowering caspase-1 cleavage and interleukin-1β (IL-1β) secretion. Inhibiting PDHK reverses NLRP3 inflammasome-induced metabolic reprogramming, enhances autophagy, promotes mitochondrial fusion over fission, preserves crista ultrastructure, and attenuates mitochondrial reactive oxygen species (ROS) production. The suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of its canonical role as a pyruvate dehydrogenase regulator. Our study suggests a non-canonical role of mitochondrial PDHK in promoting mitochondrial stress and supporting NLRP3 inflammasome activation during acute inflammation.
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    The Emerging Role of Inflammasomes as Central Mediators in Inflammatory Bladder Pathology.
    (Current urology, 2018-02) Inouye, Brian M; Hughes, Francis M; Sexton, Stephanie J; Purves, J Todd
    Irritative voiding symptoms (e.g. increased frequency and urgency) occur in many common pathologic conditions such as urinary tract infections and bladder outlet obstruction, and these conditions are well-established to have underlying inflammation that directly triggers these symptoms. However, it remains unclear as to how such diverse stimuli individually generate a common inflammatory process. Jürg Tschopp provided substantial insight into this conundrum when, working with extracts from THP-1 cells, he reported the existence of the inflammasome. He described it as a structure that senses multiple diverse signals from intracellular/extracellular sources and pathogens and triggers inflammation by the maturation and release of the pro-inflammatory cytokines interleukin-1β and interleukin-18. Recently, many of these sensors were found in the bladder and the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3, has been shown to be a central mediator of inflammation in several urological diseases. In this review, we introduce the nucleotide-binding domain, leucine-rich-containing family, pyrin domaincontaining-3 inflammasome, highlight its emerging role in several common urologic conditions, and speculate on the potential involvement of other inflammasomes in bladder pathology.
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    The NLRP3 Inflammasome Mediates Inflammation Produced by Bladder Outlet Obstruction.
    (The Journal of urology, 2016-05) Hughes, Francis M; Hill, Hayden M; Wood, Case M; Edmondson, Andrew T; Dumas, Aliya; Foo, Wen-Chi; Oelsen, James M; Rac, Goran; Purves, J Todd
    While bladder outlet obstruction 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. NLRs (NOD-like receptors) and the structures that 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 assessed the role of the NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome in bladder dysfunction resulting from bladder outlet obstruction.Bladder outlet obstruction was created in female rats by inserting a 1 mm outer diameter transurethral catheter, tying a silk ligature around the urethra and removing the catheter. Untreated and sham operated rats served as controls. Rats with bladder outlet obstruction were given vehicle (10% ethanol) or 10 mg/kg glyburide (a NLRP3 inhibitor) orally daily for 12 days. Inflammasome activity, bladder hypertrophy, inflammation and bladder function (urodynamics) were assessed.Bladder outlet obstruction increased urothelial inflammasome activity, bladder hypertrophy and inflammation, and decreased voided volume. Glyburide blocked inflammasome activation, reduced hypertrophy and prevented inflammation. The decrease in voided volume was also attenuated by glyburide mechanistically as an increase in detrusor contraction duration and voiding period.Results suggest the importance of the NLRP3 inflammasome in the induction of inflammation and bladder dysfunction secondary to bladder outlet obstruction. Arresting these processes with NLRP3 inhibitors may prove useful to treat the symptoms that they produce.
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    The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation.
    (PLoS pathogens, 2016-12-02) Ratner, Dmitry; Orning, M Pontus A; Proulx, Megan K; Wang, Donghai; Gavrilin, Mikhail A; Wewers, Mark D; Alnemri, Emad S; Johnson, Peter F; Lee, Bettina; Mecsas, Joan; Kayagaki, Nobuhiko; Goguen, Jon D; Lien, Egil
    Type III secretion systems (T3SS) are central virulence factors for many pathogenic Gram-negative bacteria, and secreted T3SS effectors can block key aspects of host cell signaling. To counter this, innate immune responses can also sense some T3SS components to initiate anti-bacterial mechanisms. The Yersinia pestis T3SS is particularly effective and sophisticated in manipulating the production of pro-inflammatory cytokines IL-1β and IL-18, which are typically processed into their mature forms by active caspase-1 following inflammasome formation. Some effectors, like Y. pestis YopM, may block inflammasome activation. Here we show that YopM prevents Y. pestis induced activation of the Pyrin inflammasome induced by the RhoA-inhibiting effector YopE, which is a GTPase activating protein. YopM blocks YopE-induced Pyrin-mediated caspase-1 dependent IL-1β/IL-18 production and cell death. We also detected YopM in a complex with Pyrin and kinases RSK1 and PKN1, putative negative regulators of Pyrin. In contrast to wild-type mice, Pyrin deficient mice were also highly susceptible to an attenuated Y. pestis strain lacking YopM, emphasizing the importance of inhibition of Pyrin in vivo. A complex interplay between the Y. pestis T3SS and IL-1β/IL-18 production is evident, involving at least four inflammasome pathways. The secreted effector YopJ triggers caspase-8- dependent IL-1β activation, even when YopM is present. Additionally, the presence of the T3SS needle/translocon activates NLRP3 and NLRC4-dependent IL-1β generation, which is blocked by YopK, but not by YopM. Taken together, the data suggest YopM specificity for obstructing the Pyrin pathway, as the effector does not appear to block Y. pestis-induced NLRP3, NLRC4 or caspase-8 dependent caspase-1 processing. Thus, we identify Y. pestis YopM as a microbial inhibitor of the Pyrin inflammasome. The fact that so many of the Y. pestis T3SS components are participating in regulation of IL-1β/IL-18 release suggests that these effects are essential for maximal control of innate immunity during plague.