MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition

Coll, Rebecca C.; Hill, J. R.; Day, Christopher J.; Zamoshnikova, Alina; Boucher, Dave; Massey, Nicholas L.; Chitty, Jessica L.; Fraser, James A.; Jennings, Michael P.; Robertson, Avril A. B.; Schroder, Kate

doi:10.1038/s41589-019-0277-7

Cited by 691 publications

(519 citation statements)

References 31 publications

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“…As a priming signal, we showed that either incubation of macrophages or intranasal treatment of mouse with ESAT-6 induced pro-IL-1β expression, consistent with our previous reports that ESAT-6 stimulates macrophage production of inflammatory cytokine and chemokine (19, 38). As an activation signal, our data with MCC950, a novel selective NLRP3 inhibitor (23, 24), showed that Mtb stimulates mature IL-1β production by macrophages in an NLRP3 dependent manner, consistent with the previous study [16]. We have also shown previously with human monocyte derived dendritic cells that caspase-1 is required for ESAT-6 mediated production of IL-1β (20).…”

Section: Discussionsupporting

confidence: 91%

Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

Jung

Vankayalapati

Samten

2020

Preprint

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TX 75708-3154, phone 29 (903)-877-7665, fax (903) 877-5516, buka.samten@uthct.edu 30 4. Acknowledgment: We thank Dr. Charles A. Dinarello for his thoughtful guidance and 31 discussions.32 5. Brief summary: Mycobacterium tuberculosis stimulated the production of IL-1β by 33 macrophages and in mouse lungs with the activation of NLRP3 and K+ efflux in an ESAT-6 34 dependent manner with the involvement of SAA3. 35 36 37 38 39 40 41 42 43 44 45 46 3 ABSTRACT 47To explore interleukin (IL)-1β production in tuberculosis, we infected mouse bone marrow-derived 48 macrophages (BMDM) with Mycobacterium tuberculosis (Mtb) H37Rv, its early secreted antigenic target 49 protein of 6 kDa (ESAT-6) gene deletion (H37Rv:∆3875) or complemented strain (H37Rv:∆3875C) and 50 evaluated IL-1β production. H37Rv induced significantly increased IL-1β production by BMDMs 51 compared to non-infected BMDMs. In contrast, H37Rv:∆3875 induced significantly less mature IL-1β 52 production despite eliciting comparable levels of pro-IL-1β and IL-8 from BMDMs compared to H37Rv 53 and H37Rv:∆3875C. Blocking either NLRP3 or K + efflux diminished H37Rv-induced IL-1β production 54 by BMDMs. Infection of mice intranasally with H37Rv:∆3875 induced less IL-1β production in the lungs 55 compared with H37Rv.Intranasal delivery of ESAT-6 but not CFP10 induced production of IL-1β in 56 mouse lungs and RNA-Seq analysis identified serum amyloid A (SAA) 3 as one of the highly expressed 57 genes in mouse lungs. Infection of mice with H37Rv but not H37Rv:∆3875 induced expression of lung 58 SAA3 mRNA and protein, consistent with the effect of intranasal delivery of ESAT-6. Silencing SAA3 59 reduced Mtb-induced IL-1β production by BMDMs. We conclude that the production of SAA3 is required 60 for Mtb stimulated IL-1β production by macrophages in tuberculosis infection. 61 62 63 64 65 66 67 68 69 70Tuberculosis (TB) caused around 1.2 million deaths among HIV-negative people and an additional 71 251,000 deaths among HIV-positive people in 2018 (1), which is mainly due to the lack of a detailed 72 understanding of the molecular mechanisms of interactions between immune cells and the pathogen, 73 Mycobacterium tuberculosis (Mtb). Improved understanding of the host-pathogen interaction will lead to 74 an effective TB vaccine design and an identification of novel drug targets to improve clinical management 75 of drug-resistant TB infections. Macrophages play critical roles in tuberculosis infection as both host cells 76 providing intracellular niche for Mtb infection and growth and effector immune cells fighting against Mtb 77infection by communicating with other immune effector cells by producing different cytokines (2). 78Although IL-1β production by macrophages is pivotal for protection against TB infection (3, 4), several 79 clinical reports showed that IL-1β is also involved in TB pathogenesis. There is significantly increased 80 IL-1β mRNA in the alveolar macrophages and IL-1β protein in bronchoalveolar lavage fluid of TB 81 patients compared with healthy controls (5...

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Section: Discussionsupporting

confidence: 91%

Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

Jung

Vankayalapati

Samten

2020

Preprint

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Section: Inflammasome‐targeted Therapies In Arthritic Diseasesmentioning

confidence: 99%

“…The compound MCC950 (also known as CRID3) is the NLRP3 inhibitor that has been the most studied to date . MCC950 inhibits NLRP3 by directly interacting with the NLRP3 ATPase domain, thereby blocking ATP hydrolysis and NLRP3 oligomerization . Several studies have shown therapeutic efficacy of MCC950 in a variety of preclinical mouse models, including atherosclerosis, experimental autoimmune encephalomyelitis, diabetes, steatohepatitis, and colitis .…”

Section: Inflammasome‐targeted Therapies In Arthritic Diseasesmentioning

confidence: 99%

“…151,152 MCC950 inhibits NLRP3 by directly interacting with the NLRP3 ATPase domain, thereby blocking ATP hydrolysis and NLRP3 oligomerization. 151,153 Several studies have shown therapeutic efficacy of MCC950 in a variety of preclinical mouse models, including atherosclerosis, experimental autoimmune encephalomyelitis, diabetes, steatohepatitis, and colitis. 17 First, before its identification as a NLRP3 targeting molecule, MCC950 was discovered as an inhibitor of IL-1β activation.…”

Section: Nlrp3 Inhibitorsmentioning

confidence: 99%

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Inflammasomes contributing to inflammation in arthritis

Spel

Martinon

2020

Immunological Reviews

125

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Inflammasomes are intracellular multiprotein signaling platforms that initiate inflammatory responses in response to pathogens and cellular damage. Active inflammasomes induce the enzymatic activity of caspase‐1, resulting in the induction of inflammatory cell death, pyroptosis, and the maturation and secretion of inflammatory cytokines IL‐1β and IL‐18. Inflammasomes are activated in many inflammatory diseases, including autoinflammatory disorders and arthritis, and inflammasome‐specific therapies are under development for the treatment of inflammatory conditions. In this review, we outline the different inflammasome platforms and recent findings contributing to our knowledge about inflammasome biology in health and disease. In particular, we discuss the role of the inflammasome in the pathogenesis of arthritic diseases, including rheumatoid arthritis, gout, ankylosing spondylitis, and juvenile idiopathic arthritis, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases.

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“…113 The NLRP3 inflammasome induces neuroinflammation and drives PD pathogenesis, as murine models of PD are protected from disease by Nlrp3 deficiency or dosing with MCC950, 38 a small-molecule NLRP3 inhibitor. 114,115 Excitingly, MCC950 suppressed disease in a murine model of PD in which dopaminergic neurons are deficient in TFAM (MitoPark model). 38 This highlights NLRP3 inhibition as a promising therapeutic strategy for the treatment of PD and other diseases involving mitochondrial dysfunction.…”

Section: Mitochondrial Disruption and Nlrp3 Inflammasome Activity Inmentioning

confidence: 99%

The rOX‐stars of inflammation: links between the inflammasome and mitochondrial meltdown

Holley

Schroder

2020

Clin & Trans Imm

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The nod-like receptor protein 3 (NLRP3) inflammasome drives inflammation in response to mitochondrial dysfunction. As metabolic powerhouses with prokaryotic ancestry, mitochondria are a cache for danger-associated molecular patterns and pathogen-associated molecular pattern-like molecules that elicit potent innate immune responses. Persistent mitochondrial damage caused by infection, or genetic or environmental factors, can lead to inappropriate or sustained inflammasome signalling. Here, we review the features of mitochondria that drive inflammatory signalling, with a particular focus on mitochondrial activation of the NLRP3 inflammasome. Given that mitochondrial network dynamics, metabolic activity and redox state are all intricately linked to each other and to NLRP3 inflammasome activity, we highlight the importance of a holistic approach to investigations of NLRP3 activation by dysfunctional mitochondria.

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MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition

Cited by 691 publications

References 31 publications

Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

Inflammasomes contributing to inflammation in arthritis

The rOX‐stars of inflammation: links between the inflammasome and mitochondrial meltdown

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