A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

被引：2181

作者：

Coll, Rebecca C. ^{[1
,2
]}

Robertson, Avril A. B. ^{[2
]}

Chae, Jae Jin ^{[3
]}

Higgins, Sarah C. ^{[1
]}

Munoz-Planillo, Raul ^{[4
,5
]}

Inserra, Marco C. ^{[2
,6
]}

Vetter, Irina ^{[2
,6
]}

Dungan, Lara S. ^{[1
]}

Monks, Brian G. ^{[7
]}

Stutz, Andrea ^{[7
]}

Croker, Daniel E. ^{[2
]}

Butler, Mark S. ^{[2
]}

Haneklaus, Moritz ^{[1
]}

Sutton, Caroline E. ^{[1
]}

Nunez, Gabriel ^{[4
,5
]}

Latz, Eicke ^{[7
,8
,9
]}

Kastner, Daniel L. ^{[3
]}

Mills, Kingston H. G. ^{[1
]}

Masters, Seth L. ^{[10
]}

Schroder, Kate ^{[2
]}

Cooper, Matthew A. ^{[2
]}

O'Neill, Luke A. J. ^{[1
]}

机构：

[1] Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Sch Biochem & Immunol, Dublin 2, Ireland

[2] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[3] NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA

[4] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA

[5] Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI USA

[6] Univ Queensland, Sch Pharm, Brisbane, Qld, Australia

[7] Univ Bonn, Univ Hosp, Inst Innate Immun, Bonn, Germany

[8] Univ Massachusetts, Sch Med, Dept Infect Dis & Immunol, Worcester, MA USA

[9] German Ctr Neurodegenerat Dis, Bonn, Germany

[10] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia

来源：

NATURE MEDICINE | 2015年 / 21卷 / 03期

基金：

欧洲研究理事会; 英国医学研究理事会; 澳大利亚研究理事会; 美国国家卫生研究院; 爱尔兰科学基金会;

关键词：

DIFFERENTIAL REQUIREMENT; NALP3; INFLAMMASOME; AUTOIMMUNE ENCEPHALOMYELITIS; CYTOPLASMIC DNA; CELL-DEATH; T-CELLS; ACTIVATION; IL-1-BETA; INTERLEUKIN-1; MECHANISMS;

D O I：

10.1038/nm.3806

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1 beta (IL-1 beta) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.

引用

页码：248 / +

页数：10

共 59 条

[1] Dimethyl sulfoxide inhibits NLRP3 inflammasome activation [J].

Ahn, Huijeong ;

Kim, Jeeyoung ;

Jeung, Eui-Bae ;

Lee, Geun-Shik .

IMMUNOBIOLOGY, 2014, 219 (04) :315-322

[2] The Inflammasomes in Kidney Disease [J].

Anders, Hans-Joachim ;

Muruve, Daniel A. .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2011, 22 (06) :1007-1018

[3] ATP-sensitive potassium channelopathies: focus on insulin secretion [J].

Ashcroft, FM .

JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (08) :2047-2058

[4] Cutting Edge: Reactive Oxygen Species Inhibitors Block Priming, but Not Activation, of the NLRP3 Inflammasome [J].

Bauernfeind, Franz ;

Bartok, Eva ;

Rieger, Anna ;

Franchi, Luigi ;

Nunez, Gabriel ;

Hornung, Veit .

JOURNAL OF IMMUNOLOGY, 2011, 187 (02) :613-617

[5] Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin [J].

Boyden, ED ;

Dietrich, WF .

NATURE GENETICS, 2006, 38 (02) :240-244

[6] Differential Requirement for Caspase-1 Autoproteolysis in Pathogen-Induced Cell Death and Cytokine Processing [J].

Broz, Petr ;

von Moltke, Jakob ;

Jones, Jonathan W. ;

Vance, Russell E. ;

Monack, Denise M. .

CELL HOST & MICROBE, 2010, 8 (06) :471-483

[7] Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies [J].

Brydges, Susannah D. ;

Broderick, Lori ;

McGeough, Matthew D. ;

Pena, Carla A. ;

Mueller, James L. ;

Hoffman, Hal M. .

JOURNAL OF CLINICAL INVESTIGATION, 2013, 123 (11) :4695-4705

[8] Inflammasome-Mediated Disease Animal Models Reveal Roles for Innate but Not Adaptive Immunity [J].

Brydges, Susannah D. ;

Mueller, James L. ;

McGeough, Matthew D. ;

Pena, Carla A. ;

Misaghi, Amirhossein ;

Gandhi, Chhavi ;

Putnam, Chris D. ;

Boyle, David L. ;

Firestein, Gary S. ;

Horner, Anthony A. ;

Soroosh, Pejman ;

Watford, Wendy T. ;

O'Shea, John J. ;

Kastner, Daniel L. ;

Hoffman, Hal M. .

IMMUNITY, 2009, 30 (06) :875-887

[9] An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome [J].

Buerckstuemmer, Tilmann ;

Baumann, Christoph ;

Blueml, Stephan ;

Dixit, Evelyn ;

Duernberger, Gerhard ;

Jahn, Hannah ;

Planyavsky, Melanie ;

Bilban, Martin ;

Colinge, Jacques ;

Bennett, Keiryn L. ;

Superti-Furga, Giulio .

NATURE IMMUNOLOGY, 2009, 10 (03) :266-272

[10] The Cytokine Release Inhibitory Drug CRID3 Targets ASC Oligomerisation in the NLRP3 and AIM2 Inflammasomes [J].

Coll, Rebecca C. ;

O'Neill, Luke A. J. .

PLOS ONE, 2011, 6 (12)

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