The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction

Hout, Gerardus P.J. van; Bosch, Lena; Ellenbroek, Guilielmus H.J.M.; Haan, Judith J. de; Solinge, Wouter W. van; Cooper, Matthew A.; Arslan, Fatih; Jager, Saskia C.A. de; Robertson, Avril A. B.; Pasterkamp, Gérard; Hoefer, Imo E.

doi:10.1093/eurheartj/ehw247

Cited by 187 publications

(161 citation statements)

References 35 publications

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“…Because the priming step of inflammasome activation is largely mediated by NF-kB, and because aPC inhibits NF-kB activity, the proposed function of aPC in restricting inflammasome priming is plausible. 48,49 Considering the results obtained here using aPC and parmodulin-2 or recent studies using small-compound Nlrp3 inhibitors, 50 targeting both steps of Nlrp3 inflammasome seems to be therapeutically feasible. On the basis of these observations, we propose that simultaneously restricting the priming (induction of Nlrp3 expression) and activation (formation of the inflammasome complex) steps may be superior to inhibition of IL-1 receptor signaling or caspases.…”

Section: Discussionmentioning

confidence: 79%

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

Nazir

Gadi

Al‐Dabet

et al. 2017

Blood

135

124

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Section: Discussionmentioning

confidence: 79%

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

Nazir

Gadi

Al‐Dabet

et al. 2017

Blood

135

124

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“…It can be given by oral, intravenous, and i.p. routes and is effective at doses ranging from 4 to 20 mg/kg in mouse models of autoimmune disease (experimental autoimmune encephalitis) (14), diseases of constitutive NLRP3 activation (cryopyrin-associated periodic syndrome) (14), and disorders in which NLRP3 has been shown to play an important role [including cardiac infarction (25) and non-alcoholic steatohepatitis (26)]. In vitro treatment of IAV-infected THP-1 macrophages with MCC950 confirmed that IAV-induced NLRP3 inflammasome activation is effectively inhibited with this molecule.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the NOD-Like Receptor Protein 3 Inflammasome Is Protective in Juvenile Influenza A Virus Infection

et al. 2017

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Influenza A virus (IAV) is a significant cause of life-threatening lower respiratory tract infections in children. Antiviral therapy is the mainstay of treatment, but its effectiveness in this age group has been questioned. In addition, damage inflicted on the lungs by the immune response to the virus may be as important to the development of severe lung injury during IAV infection as the cytotoxic effects of the virus itself. A crucial step in the immune response to IAV is activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and the subsequent secretion of the inflammatory cytokines, interleukin-1β (IL-1β), and interleukin-18 (IL-18). The IAV matrix 2 proton channel (M2) has been shown to be an important activator of the NLRP3 inflammasome during IAV infection. We sought to interrupt this ion channel-mediated activation of the NLRP3 inflammasome through inhibition of NLRP3 or the cytokine downstream from its activation, IL-1β. Using our juvenile mouse model of IAV infection, we show that inhibition of the NLRP3 inflammasome with the small molecule inhibitor, MCC950, beginning 3 days after infection with IAV, improves survival in juvenile mice. Treatment with MCC950 reduces NLRP3 levels in lung homogenates, decreases IL-18 secretion into the alveolar space, and inhibits NLRP3 inflammasome activation in alveolar macrophages. Importantly, inhibition of the NLRP3 inflammasome with MCC950 does not impair viral clearance. In contrast, inhibition of IL-1β signaling with the IL-1 receptor antagonist, anakinra, is insufficient to protect juvenile mice from IAV. Our findings suggest that targeting the NLRP3 inflammasome in juvenile IAV infection may improve disease outcomes in this age group.

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“…Evans blue-TTC double staining is a frequently used method to show the surviving area and infarct size. 24,25 The infarcted myocardium cannot receive blood from the coronary artery so will not be dyed blue by Evans blue, which was injected through ascending aorta. The totally dead myocardium cannot be dyed red by TTC.…”

Section: Discussionmentioning

confidence: 99%

MR targeted imaging for the expression of tenascin‐C in myocardial infarction in vivo

Song

et al. 2016

Magnetic Resonance Imaging

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The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction

Abstract: NLRP3-inflammasome inhibition reduces infarct size and preserves cardiac function in a randomized, blinded translational large animal MI model. Hence, NLRP3-inflammasome inhibition may have therapeutic potential in acute MI patients.

Cited by 187 publications

References 35 publications

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

Cytoprotective activated protein C averts Nlrp3 inflammasome–induced ischemia-reperfusion injury via mTORC1 inhibition

Inhibition of the NOD-Like Receptor Protein 3 Inflammasome Is Protective in Juvenile Influenza A Virus Infection

MR targeted imaging for the expression of tenascin‐C in myocardial infarction in vivo

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