Inhibiting the Inflammasome: A Chemical Perspective

Baldwin, Alex G.; Brough, David; Freeman, Sally

doi:10.1021/acs.jmedchem.5b01091

Cited by 121 publications

(102 citation statements)

References 183 publications

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“…Early inhibition of inflammasome activation using small-molecule inhibitors of NLRP-3 may be an attractive target in ARDS, and it has been demonstrated that A438079—an antagonist of the upstream P2X7 receptor—mitigates injury in a mouse model of ALI. 29,30 …”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Hypoxic Alveolar Epithelial Cells After Lung Contusion Indicates an Important Role for HIF-1α

et al. 2018

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Objective To understand the fate and regulation of hypoxic type II alveolar epithelial cells (AECs) after lung contusion (LC). Background LC due to thoracic trauma is a major risk factor for the development of acute respiratory distress syndrome. AECs have recently been implicated as a primary driver of inflammation in LC. The main pathological consequence of LC is hypoxia, and a key mediator of adaptation to hypoxia is hypoxia-inducible factor (HIF)-1. We have recently published that HIF-1α is a major driver of acute inflammation after LC through type II AEC. Methods LC was induced in wild-type mice (C57BL/6), luciferase-based hypoxia reporter mice (ODD-Luc), and HIF-1α conditional knockout mice. The degree of hypoxia was assessed using hypoxyprobe and in vivo imaging system. The fate of hypoxic AEC was evaluated by luciferase dual staining with caspases-3 and Ki-67, terminal deoxynucleotidyl transferase dUTP nick end labeling, and flow cytometry with ApoStat. NLRP-3 expression was determined by western blot. Laser capture microdissection was used to isolate AECs in vivo, and collected RNA was analyzed by Q-PCR for HIF-related pathways. Results Global hypoxia was present after LC, but hypoxic foci were not uniform. Hypoxic AECs preferentially undergo apoptosis. There were significant reductions in NLRP-3 in HIF-1α conditional knockout mice. The expression of proteins involved in HIF-related pathways and inflammasome activation were significantly increased in hypoxic AECs. Conclusions These are the first in vivo data to identify, isolate, and characterize hypoxic AECs. HIF-1α regulation through hypoxic AECs is critical to the initiation of acute inflammation after LC.

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Section: Discussionmentioning

confidence: 99%

Molecular Characterization of Hypoxic Alveolar Epithelial Cells After Lung Contusion Indicates an Important Role for HIF-1α

et al. 2018

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“…[18] This evidence has increased the interest in the discovery of agents able to prevent inflammasome activation, which is regarded as a promising therapeutic strategy to decrease chronic inflammation and associated damage in different pathological settings. To date, different approaches have been pursued, [19] among which reversible or irreversible modification of reactive cysteine (Cys) residues of relevant proteins seems to be the NLRP3 inflammasome plays a key role in the intracellular activation of caspase-1, processing of pro-inflammatory interleukin-1b (IL-1b), and pyroptotic cell death cascade. The overactivation of NLRP3 is implicated in the pathogenesis of autoinflammatory diseases, known as cryopyrin-associated periodic syndromes (CAPS), and in the progression of several diseases, such as atherosclerosis, type-2 diabetes, gout, and Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Acrylamide Derivatives as Direct NLRP3 Inflammasome Inhibitors

et al. 2016

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NLRP3 inflammasome plays a key role in the intracellular activation of caspase-1, processing of pro-inflammatory interleukin-1β (IL-1β), and pyroptotic cell death cascade. The overactivation of NLRP3 is implicated in the pathogenesis of autoinflammatory diseases, known as cryopyrin-associated periodic syndromes (CAPS), and in the progression of several diseases, such as atherosclerosis, type-2 diabetes, gout, and Alzheimer's disease. In this study, the synthesis of acrylamide derivatives and their pharmaco-toxicological evaluation as potential inhibitors of NLRP3-dependent events was undertaken. Five hits were identified and evaluated for their efficiency in inhibiting IL-1β release from different macrophage subtypes, including CAPS mutant macrophages. The most attractive hits were tested for their ability to inhibit NLRP3 ATPase activity on human recombinant NLRP3. This screening allowed the identification of 14, 2-(2-chlorobenzyl)-N-(4-sulfamoylphenethyl)acrylamide, which was able to concentration-dependently inhibit NLRP3 ATPase with an IC50 value of 74 μm. The putative binding pose of 14 in the ATPase domain of NLRP3 was also proposed.

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“…Putative inhibitors of the NLRP3 inflammasome pathway have been described, including glyburide (glibenclamide), Bay 11-7082, b-hydroxybutyrate, and parthenolide (3,4,20). In 2001, Perregaux et al (21) described a class of diarylsulfonylurea compounds with structural similarities to glyburide that are capable of inhibiting LPS plus ATP-induced processing and release of IL-1b.…”

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confidence: 99%

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

138

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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Inhibiting the Inflammasome: A Chemical Perspective

Cited by 121 publications

References 183 publications

Molecular Characterization of Hypoxic Alveolar Epithelial Cells After Lung Contusion Indicates an Important Role for HIF-1α

Molecular Characterization of Hypoxic Alveolar Epithelial Cells After Lung Contusion Indicates an Important Role for HIF-1α

Design, Synthesis, and Evaluation of Acrylamide Derivatives as Direct NLRP3 Inflammasome Inhibitors

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

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