NLRP3 Localizes to the Tubular Epithelium in Human Kidney and Correlates With Outcome in IgA Nephropathy

Chun, Justin; Chung, Hyunsoo; Wang, Xiangyu; Barry, Rebecca; Taheri, Zahra; Platnich, Jaye M.; Ahmed, Sofia B.; Trpkov, Kiril; Hemmelgarn, Brenda R.; Benediktsson, Hallgrímur; James, Matthew T.; Muruve, Daniel A.

doi:10.1038/srep24667

Cited by 57 publications

(41 citation statements)

References 42 publications

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“…To a lesser degree, some podocytes in patients with IgA nephropathy were shown to express caspase 1. The latter finding corroborates the recent observation that NLRP3 localized to the tubular epithelium in human kidneys correlates with outcome in IgA nephropathy (23).…”

Section: Discussionsupporting

confidence: 91%

Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

Guo

Wang

et al. 2017

Arthritis & Rheumatology

155

107

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Objective Development of proteinuria in lupus nephritis (LN) is associated with podocyte dysfunction. The NLRP3 inflammasome has been implicated in the pathogenesis of LN. This study investigates whether NLRP3 inflammasome activation is involved in the development of podocyte injury in LN. Methods A fluorescence-labeled caspase-1 inhibitor probe was used to detect the activation of NLRP3 inflammasomes in podocytes in lupus-prone NZM2328 mice and in renal biopsies from LN patients. MCC950, a selective inhibitor of NLRP3, was used to treat NZM2328 mice. Proteinuria, ultrastructure of podocytes and renal pathology were evaluated. In vitro, sera from diseased NZM2328 mice were used to stimulate a podocyte cell line and cells were subjected to flow cytometry analysis. Results NLRP3 inflammasomes were activated in podocytes of lupus-prone mice and LN patients. Inhibition of NLRP3 with MCC950 ameliorated proteinuria, renal histological lesions and podocyte foot process effacement in lupus-prone mice. In vitro, sera from NZM2328 diseased mice activated NLRP3 inflammasomes in the podocyte cell line through reactive oxygen species (ROS) production. Conclusion NLRP3 inflammasomes were activated in podocytes of both LN patients and in lupus-prone mice. Activation of NLRP3 is involved in the pathogenesis of podocyte injuries and the development of proteinuria in LN.

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Section: Discussionsupporting

confidence: 91%

Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

Guo

Wang

et al. 2017

Arthritis & Rheumatology

155

107

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“…Very recently, Chun et al 18. reported that decreased expression of NLRP3 mRNA and protein in kidney biopsies of IgAN patients.…”

Section: Discussionmentioning

confidence: 99%

“…Innate immunity is triggered by endogenous or environmental insults through assembly of the NLRP3 inflammasome1012, which has been observed in many cell types, such as macrophages, dendritic cells (DCs), T cells, and some epithelial cells101112. Recently, several studies have suggested that NLRP3 inflammasome may be implicated in the pathogenesis of IgAN in pateints161718. However, the causal-relationship between the inflammasome and the pathogenesis of IgAN is yet to be determined.…”

mentioning

confidence: 99%

NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy

Tsai

Hua

Chen

et al. 2017

Sci Rep

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We have previously showed that IL-1β is involved in the pathogenesis of both spontaneously occurring and passively induced IgA nephropathy (IgAN) models. However, the exact causal-relationship between NLRP3 inflammasome and the pathogenesis of IgAN remains unknown. In the present study, we showed that [1] IgA immune complexes (ICs) activated NLRP3 inflammasome in macrophages involving disruption of mitochondrial integrity and induction of mitochondrial ROS, bone marrow-derived dendritic cells (BMDCs) and renal intrinsic cells; [2] knockout of NLRP3 inhibited IgA ICs-mediated activation of BMDCs and T cells; and [3] knockout of NLRP3 or a kidney-targeting delivery of shRNA of NLRP3 improved renal function and renal injury in a mouse IgAN model. These results strongly suggest that NLRP3 inflammasome serves as a key player in the pathogenesis of IgAN partly through activation of T cells and mitochondrial ROS production and that a local, kidney-targeting suppression of NLRP3 be a therapeutic strategy for IgAN.

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“…Statistical analysis was performed also using the software RT 2 profiler PCR Array Data Analysis (Qiagen minutes and at baseline and 30 and 90 minutes, respectively, in order to evaluate ubiquitin-mediated degradation. The ubiquitin inhibitor MG132 (M8699, Sigma-Aldrich) was added in order to block ubiquitin-mediated degradation, and NLRP3 or P2X7R was quantified at the same time points described above (44,45).…”

Section: Qrt-pcr Analysismentioning

confidence: 99%

P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes

D’Addio

Vergani

Potena

et al. 2018

Journal of Clinical Investigation

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Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of-function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation. Transient NLRP3 silencing in nonmutant T cells or overexpression in mutant T cells normalized the Th profile. Interestingly, IL-17 blockade reduced Th17 skewing of human T cells in vitro and abrogated the severe allograft vasculopathy and abnormal Th17 generation observed in preclinical models in which P2X7R was genetically deleted. This P2X7R intracellular region mutation thus impaired the modulatory effects of P2X7R on NLRP3 expression and function in T cells and led to NLRP3 dysregulation and Th17 skewing, delineating a high-risk group of cardiac-transplanted patients who may benefit from personalized therapy.

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NLRP3 Localizes to the Tubular Epithelium in Human Kidney and Correlates With Outcome in IgA Nephropathy

Cited by 57 publications

References 42 publications

Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis

NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy

P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes

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