Pigment Nephropathy: Novel Insights into Inflammasome-Mediated Pathogenesis

Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased oxidative stress and inflammation. Haem is associated with inflammation in sterile and infectious conditions, contributing to the pathogenesis of many disorders such as rhabdomyolysis and haemolytic diseases. In fact, haem appears to be a signaling molecule that is able to activate the inflammasome pathway. Recent studies highlight a pathogenic function for haem in triggering inflammatory responses through the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Among the inflammasome multiprotein complexes, the NLRP3 inflammasome has been the most widely characterized as a trigger of inflammatory caspases and the maturation of interleukin-18 and -1β. In the present review, we discuss the latest evidence on the importance of inflammasome-mediated inflammation in pigment nephropathy. Finally, we highlight the potential role of inflammasome inhibitors in the prophylaxis and treatment of pigment nephropathy.

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Pigment Nephropathy: Novel Insights into Inflammasome-Mediated Pathogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms20081997 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1997 ◽

Cited By ~ 4

Author(s):

Kurt T. K. Giuliani ◽

Andrew J. Kassianos ◽

Helen Healy ◽

Pedro H. F. Gois

Keyword(s):

Nlrp3 Inflammasome ◽

Potential Role ◽

Inflammatory Responses ◽

Receptor Protein ◽

Nucleotide Binding Domain ◽

Renal Vasoconstriction ◽

Signalling Molecule ◽

Pigment Nephropathy ◽

Inflammatory Caspases

Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased oxidative stress and inflammation. Haem is associated with inflammation in sterile and infectious conditions, contributing to the pathogenesis of many disorders such as rhabdomyolysis and haemolytic diseases. In fact, haem appears to be a signalling molecule that is able to activate the inflammasome pathway. Recent studies highlight a pathogenic function for haem in triggering inflammatory responses through the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Among the inflammasome multiprotein complexes, the NLRP3 inflammasome has been the most widely characterized as a trigger of inflammatory caspases and the maturation of interleukin-18 and -1β. In the present review, we discuss the latest evidence on the importance of inflammasome-mediated inflammation in pigment nephropathy. Finally, we highlight the potential role of inflammasome inhibitors in the prophylaxis and treatment of pigment nephropathy.

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Vitamin D and the NLRP3 Inflammasome

Applied Sciences ◽

10.3390/app10238462 ◽

2020 ◽

Vol 10 (23) ◽

pp. 8462

Author(s):

Matthew Tunbridge ◽

Pedro Henrique França Gois

Keyword(s):

Vitamin D ◽

Nlrp3 Inflammasome ◽

Clinical Evidence ◽

The Body ◽

Receptor Protein ◽

Inflammasome Activation ◽

Nucleotide Binding Domain ◽

Nlrp3 Inflammasome Activation ◽

Improved Outcomes

Vitamin D (VD) is a steroid hormone classically known for its key role in maintaining calcium homeostasis in the body. VD also has important immunomodulatory functions. This review explores evidence for a role of VD in attenuating the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Dysregulated and inappropriate NLRP3 inflammasome activation occurs in a range of human diseases, including autoinflammatory disorders, metabolic disorders, and infections. VD appears to mediate its effects by binding of the VD receptor (VDR) to the sensor protein NLRP3, inhibiting deubiquitination and downstream inflammasome assembly. Some early clinical evidence suggests improved outcomes in inflammasome-mediated disorders when VD-deficient patients are treated with supplementation therapy.

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The NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders

Mediators of Inflammation ◽

10.1155/2013/678627 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 48

Author(s):

Elisa Benetti ◽

Fausto Chiazza ◽

Nimesh S. A. Patel ◽

Massimo Collino

Keyword(s):

Chronic Inflammation ◽

Nlrp3 Inflammasome ◽

Metabolic Disorders ◽

Inflammasome Activation ◽

Nucleotide Binding Domain ◽

Metabolic Inflammation ◽

Nlrp3 Inflammasome Activation ◽

Leucine Rich Repeat Protein

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the “inflammasome,” a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1βand IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.

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Potential role of NF-κB pathway in the immuno-inflammatory responses during human cystic echinococcosis

Acta Tropica ◽

10.1016/j.actatropica.2019.105306 ◽

2020 ◽

Vol 203 ◽

pp. 105306 ◽

Cited By ~ 1

Author(s):

Sarah Tilioua ◽

Dalila Mezioug ◽

Zine-Charaf Amir-Tidadini ◽

Yacine-Miloud Medjdoub ◽

Chafia Touil-Boukoffa

Keyword(s):

Cystic Echinococcosis ◽

Potential Role ◽

Inflammatory Responses ◽

Human Cystic Echinococcosis

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The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes

Blood ◽

10.1182/blood-2018-10-844654 ◽

2019 ◽

Vol 133 (10) ◽

pp. 1039-1048 ◽

Cited By ~ 34

Author(s):

David A. Sallman ◽

Alan List

Keyword(s):

Myelodysplastic Syndromes ◽

Immune Activation ◽

Nlrp3 Inflammasome ◽

Cancer Biology ◽

Innate Immune ◽

Cell Swelling ◽

Receptor Protein ◽

Inflammasome Activation ◽

Innate Immune Activation

Abstract In cancer biology, tumor-promoting inflammation and an inflammatory microenvironment play a vital role in disease pathogenesis. In the past decade, aberrant innate immune activation and proinflammatory signaling within the malignant clone and the bone marrow (BM) microenvironment were identified as key pathogenic drivers of myelodysplastic syndromes (MDS). In particular, S100A9-mediated NOD-like receptor protein 3 (NLRP3) inflammasome activation directs an inflammatory, lytic form of cell death termed pyroptosis that underlies many of the hallmark features of the disease. This circuit and accompanying release of other danger-associated molecular patterns expands BM myeloid-derived suppressor cells, creating a feed-forward process propagating inflammasome activation. Furthermore, somatic gene mutations of varied functional classes license the NLRP3 inflammasome to generate a common phenotype with excess reactive oxygen species generation, Wnt/β-catenin–induced proliferation, cation flux-induced cell swelling, and caspase-1 activation. Recent investigations have shown that activation of the NLRP3 inflammasome complex has more broad-reaching importance, particularly as a possible disease-specific biomarker for MDS, and, mechanistically, as a driver of cardiovascular morbidity/mortality in individuals with age-related, clonal hematopoiesis. Recognition of the mechanistic role of aberrant innate immune activation in MDS provides a new perspective for therapeutic development that could usher in a novel class of disease-modifying agents.

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CD36-Mediated Lipid Accumulation and Activation of NLRP3 Inflammasome Lead to Podocyte Injury in Obesity-Related Glomerulopathy

Mediators of Inflammation ◽

10.1155/2019/3172647 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Jing Zhao ◽

Hong-liang Rui ◽

Min Yang ◽

Li-jun Sun ◽

Hong-rui Dong ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Lipid Accumulation ◽

Inflammatory Responses ◽

Regulatory Element ◽

Animal Experiments ◽

Receptor Protein ◽

Peroxisome Proliferator ◽

Podocyte Injury ◽

Peroxisome Proliferator Activated Receptor

Podocyte injury critically contributes to the pathogenesis of obesity-related glomerulopathy (ORG). Recently, lipid accumulation and inflammatory responses have been found to be involved in podocyte injury. This study is to explore their role and relationship in podocyte injury of ORG. In animal experiments, the ORG mice developed proteinuria, podocyte injury, and hypertriglyceridemia, accompanied with deregulated lipid metabolism, renal ectopic lipid deposition, activation of NOD-like receptor protein 3 (NLRP3) inflammasome, and secretion of IL-1β of the kidney. The expression of adipose differentiation-related protein (ADRP), CD36, sterol regulatory element-binding protein 1 (SREBP-1), and peroxisome proliferator-activated receptor α (PPARα) in renal tissue were increased. In in vitro cell experiments, after cultured podocytes were stimulated with leptin, similar to ORG mice, we found aggravated podocyte injury, formatted lipid droplet, increased expression of ADRP and CD36, activated NLRP3 inflammasome, and released IL-1β. In addition, after blocking CD36 with inhibitor sulfo-N-succinimidyl oleate (SSO) or CD36 siRNA, activation of NLRP3 inflammasome and release of IL-1β are downregulated, and podocyte injury was alleviated. However, after blocking NLRP3 with MCC950, although podocyte injury was alleviated and release of IL-1β was decreased, there was no change in the expression of CD36, ADRP, and intracellular lipid droplets. Taken together, our study suggests that CD36-mediated lipid accumulation and activation of NLRP3 inflammasome may be one of the potential pathogeneses of ORG podocyte injury.

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NLRP3 inflammasome in ischemic stroke: As possible therapeutic target

International Journal of Stroke ◽

10.1177/1747493019841242 ◽

2019 ◽

Vol 14 (6) ◽

pp. 574-591 ◽

Cited By ~ 21

Author(s):

Masoumeh Alishahi ◽

Maryam Farzaneh ◽

Farhoodeh Ghaedrahmati ◽

Armin Nejabatdoust ◽

Alireza Sarkaki ◽

...

Keyword(s):

Ischemic Stroke ◽

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Receptor Protein ◽

Current Evidence ◽

Related Factor ◽

Type I ◽

Micro Rnas ◽

Extracellular Environment ◽

Inflammasome Inhibitors

Inflammation is a devastating pathophysiological process during stroke, a devastating disease that is the second most common cause of death worldwide. Activation of the NOD-like receptor protein (NLRP3)-infammasome has been proposed to mediate inflammatory responses during ischemic stroke. Briefly, NLRP3 inflammasome activates caspase-1, which cleaves both pro-IL-1 and pro-IL-18 into their active pro-inflammatory cytokines that are released into the extracellular environment. Several NLRP3 inflammasome inhibitors have been promoted, including small molecules, type I interferon, micro RNAs, nitric oxide, and nuclear factor erythroid-2 related factor 2 (Nrf2), some of which are potentially efficacious clinically. This review will describe the structure and cellular signaling pathways of the NLRP3 inflammasome during ischemic stroke, and current evidence for NLRP3 inflammasome inhibitors.

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Using Network Pharmacology for Systematic Understanding of Geniposide in Ameliorating Inflammatory Responses in Colitis Through Suppression of NLRP3 Inflammasome in Macrophage by AMPK/Sirt1 Dependent Signaling

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500846 ◽

2020 ◽

Vol 48 (07) ◽

pp. 1693-1713

Author(s):

Zhichen Pu ◽

Yanhao Liu ◽

Chao Li ◽

Moadi Xu ◽

Haitang Xie ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Receptor Protein ◽

Network Pharmacology ◽

Enzyme Linked Immunosorbent Assay ◽

Cell Models ◽

Acute Colitis ◽

Raw264.7 Cell ◽

Anti Inflammatory ◽

Systematic Understanding

Ulcerative colitis is a chronic and recurrent inflammatory bowel disease mediated by immune response. Geniposide is the main active ingredient extracted from Gardenia jasminoides, which has been suggested to exert excellent efficacy on inflammatory disease. Herein, in this study, we aimed to uncover the systematic understanding of the mechanism and effects of geniposide in ameliorating inflammatory responses in colitis. In brief, the TCMSP server and GEO DataSets were used to analyze the systematic understanding of the mechanism and effects of geniposide in ameliorating inflammatory responses in colitis. Dextran Sulfate Sodium (DSS)-induced acute colitis of mice were administered with 25–100[Formula: see text]mg/kg of geniposide for 7 days by gavage. Lipopolysaccharide (LPS)-induced Bone Marrow Derived Macrophage (BMDM) cell or RAW264.7 cell models were treated with 20, 50 and 100[Formula: see text][Formula: see text]M of geniposide for 4[Formula: see text]h. Myeloperoxidase (MPO) activity and Interleukin-1[Formula: see text] (IL-1[Formula: see text] levels were measured using MPO activity kits and IL-1[Formula: see text] levels enzyme-linked immunosorbent assay (ELISA) kits, respectively. Additionally, Western blot was used to determine the relevant protein expression. As a result, Geniposide could ameliorate inflammatory responses and prevent colitis in DSS-induced acute colitis of mice by activating AMP-activated protein kinase (AMPK)/Transcription 1 (Sirt1) dependent signaling via the suppression of nod-like receptor protein 3 (NLRP3) inflammasome. Geniposide attenuated macrophage differentiation in DSS-induced acute colitis of mice. Geniposide suppressed NLRP3 inflammasome and induced AMPK/Sirt1 signaling in LPS-induced BMDM cell or RAW264.7 cell models. In mechanism studies, the inhibition of AMPK/Sirt1 attenuated the anti-inflammatory effects of geniposide in colitis. The activation of NLRP3 attenuated the anti-inflammatory effects of geniposide in colitis. Taken together, our results demonstrated that geniposide ameliorated inflammatory responses in colitis vai the suppression of NLRP3 inflammasome in macrophages by AMPK/Sirt1-dependent signaling.

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