Canonical and non-canonical effects of the NLRP3 inflammasome in kidney inflammation and fibrosis

Lorenz, Georg; Darisipudi, Murthy N.; Anders, Hans‐Joachim

doi:10.1093/ndt/gft332

Cited by 189 publications

(149 citation statements)

References 61 publications

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“…Increasing evidence implicates the NLRP3 inflammasome and its activation products IL-1b, IL-18, IL-1a, and high-mobility group box 1 in the pathogenesis of tissue injury and disease (4,8,9,(12)(13)(14)(15)44). Therefore, a potent, selective, and orally available pharmacological inhibitor of NLRP3 inflammasome should be useful for elucidating the pathogenic contributions of NLRP3 inflammasome activation and its multiple products in preclinical disease models.…”

Section: Discussionmentioning

confidence: 99%

“…We investigated the ability of CP-456,773 to inhibit NLRP3 activation induced by crystalline activators that have been associated with inflammatory diseases (2,4,9,27). In the results shown in Fig.…”

Section: Cp-456773 Inhibits Release Of Il-1b Induced With Both Solubmentioning

confidence: 99%

“…Amelioration of disease sequelae via inhibition or deficiency of NLRP3 inflammasome components or products has been demonstrated in a wide range of preclinical models, including models of autoinflammatory disease, pulmonary disease, renal disease, neurodegenerative disease, and metabolic disease (4,8,9,(12)(13)(14)(15). The contribution of the NLRP3 inflammasome to human disease is evidenced by the pathology observed in patients with cryopyrinassociated periodic syndrome (CAPS).…”

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confidence: 99%

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Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation

Primiano

Lefker

Bowman

et al. 2016

The Journal of Immunology

144

117

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A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains–containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro–IL-1β and pro–IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome–selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream–induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease.

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Section: Discussionmentioning

confidence: 99%

Section: Cp-456773 Inhibits Release Of Il-1b Induced With Both Solubmentioning

confidence: 99%

mentioning

confidence: 99%

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Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation

Primiano

Lefker

Bowman

et al. 2016

The Journal of Immunology

144

117

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“…17,18,20,[50][51][52][53] But are the inflammasome components expressed at all in the kidney and, if so, do they contribute to canonical inflammasome signaling 54,55 ? IL-1a and IL-1b are both induced by NF-ĸB signaling but still display heterogeneous expression patterns in solid organs of healthy mice.…”

Section: Data In Renal Cells: Expression Releasementioning

confidence: 99%

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

Anders

2016

JASN

Self Cite

209

152

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Kidney injury implies danger signaling and a response by the immune system. The inflammasome is a central danger recognition platform that triggers local and systemic inflammation. In immune cells, inflammasome activation causes the release of mature IL-1b and of the alarmin IL-1a. Dying cells release IL-1a also, independently of the inflammasome. Both IL-1a and IL-1b ligate the same IL-1 receptor (IL-1R) that is present on nearly all cells inside and outside the kidney, further amplifying cytokine and chemokine release. Thus, the inflammasome-IL-1a/IL-b-IL-1R system is a central element of kidney inflammation and the systemic consequences. Seminal discoveries of recent years have expanded this central paradigm of inflammation. This review gives an overview of arising concepts of inflammasome and IL-1a/b regulation in renal cells and in experimental kidney disease models. There is a pipeline of compounds that can interfere with the inflammasome-IL-1a/IL-b-IL-1R system, ranging from recently described small molecule inhibitors of NLRP3, a component of the inflammasome complex, to regulatory agency-approved IL-1-neutralizing biologic drugs. Based on strong theoretic and experimental rationale, the potential therapeutic benefits of using such compounds to block the inflammasome-IL-1a/IL-b-IL-1R system in kidney disease should be further explored.

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“…These results are consistent with other reports showing noncanonical effects of Nlrp3 in the kidney. 15,16,27,29 Next to cytokines, renal function is influenced by tubular damage and repair. Interestingly, we observed that renal apoptosis was reduced in mice lacking Nlrp3 expression in leukocytes, suggesting that leukocyte-associated Nlrp3 influences tubular epithelial apoptosis and, thereby, renal dysfunction.…”

Section: Nlrp3 Regulates Renal Repairmentioning

confidence: 99%

A Tissue-Specific Role for Nlrp3 in Tubular Epithelial Repair after Renal Ischemia/Reperfusion

Bakker

Butter

Claessen

et al. 2014

The American Journal of Pathology

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Canonical and non-canonical effects of the NLRP3 inflammasome in kidney inflammation and fibrosis

Cited by 189 publications

References 61 publications

Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation

Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

A Tissue-Specific Role for Nlrp3 in Tubular Epithelial Repair after Renal Ischemia/Reperfusion

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