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

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Cytoprotective activated protein C averts Nlrp3 inflammasome induced ischemia reperfusion injury via mTORC1 inhibition. / Nazir, Sumra; Gadi, Ihsan; Al-Dabet, Moh'd Mohanad; Elwakiel, Ahmed; Kohli, Shrey; Ghosh, Sanchita; Manoharan, Jayakumar; Ranjan, Satish; Bock, Fabian; Braun-Dullaeus, Ruediger C; Esmon, Charles T; Huber, Tobias B; Camerer, Eric; Dockendorff, Chris; Griffin, John H; Isermann, Berend; Shahzad, Khurrum.

In: BLOOD, Vol. 130, No. 24, 14.12.2017, p. 2664-2677.

Research output: SCORING: Contribution to journalSCORING: Journal articleResearchpeer-review

Harvard

Nazir, S, Gadi, I, Al-Dabet, MM, Elwakiel, A, Kohli, S, Ghosh, S, Manoharan, J, Ranjan, S, Bock, F, Braun-Dullaeus, RC, Esmon, CT, Huber, TB, Camerer, E, Dockendorff, C, Griffin, JH, Isermann, B & Shahzad, K 2017, 'Cytoprotective activated protein C averts Nlrp3 inflammasome induced ischemia reperfusion injury via mTORC1 inhibition', BLOOD, vol. 130, no. 24, pp. 2664-2677. https://doi.org/10.1182/blood-2017-05-782102

APA

Nazir, S., Gadi, I., Al-Dabet, M. M., Elwakiel, A., Kohli, S., Ghosh, S., Manoharan, J., Ranjan, S., Bock, F., Braun-Dullaeus, R. C., Esmon, C. T., Huber, T. B., Camerer, E., Dockendorff, C., Griffin, J. H., Isermann, B., & Shahzad, K. (2017). Cytoprotective activated protein C averts Nlrp3 inflammasome induced ischemia reperfusion injury via mTORC1 inhibition. BLOOD, 130(24), 2664-2677. https://doi.org/10.1182/blood-2017-05-782102

Vancouver

Bibtex

@article{377f595b30504365809775eb8f7736a5,
title = "Cytoprotective activated protein C averts Nlrp3 inflammasome induced ischemia reperfusion injury via mTORC1 inhibition",
abstract = "Cytoprotection by activated protein C (aPC) following ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation and hence conceptually cell-death forms disjunct from immunologically silent apoptosis are more likely to be relevant. As pyroptosis, cell death resulting from inflammasome activation, is typically observed in IRI we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRI. aPC treatment before or after myocardial IRI reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that Nlrp3 inflammasome activation preceded myocardial injury and apoptosis, corroborating a pathogenic role of the Nlrp3 inflammasome. The constitutively active Nlrp3(A350V) mutant abolished aPC's protective effect, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation in macrophages, cardiomyocytes, and cardiac fibroblasts via PAR-1 and mTORC1 signaling. Accordingly, inhibiting PAR-1 signaling, but not aPC's anticoagulant properties, abolished aPC's ability to restrict Nlrp3 inflammasome activity and tissue damage in myocardial IRI. Targeting biased PAR-1 signaling via parmodulin-2 restricted mTORC1 and Nlrp3 inflammasome activation and limited myocardial IRI as efficient as aPC. The relevance of aPC-mediated Nlrp3 inflammasome suppression following IRI was corroborated in renal IRI, where aPC's tissue protective effect was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1 dependent inflammasome activation and that mimicking biased aPC-PAR1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI.",
keywords = "Journal Article",
author = "Sumra Nazir and Ihsan Gadi and Al-Dabet, {Moh'd Mohanad} and Ahmed Elwakiel and Shrey Kohli and Sanchita Ghosh and Jayakumar Manoharan and Satish Ranjan and Fabian Bock and Braun-Dullaeus, {Ruediger C} and Esmon, {Charles T} and Huber, {Tobias B} and Eric Camerer and Chris Dockendorff and Griffin, {John H} and Berend Isermann and Khurrum Shahzad",
note = "Copyright {\textcopyright} 2017 American Society of Hematology.",
year = "2017",
month = dec,
day = "14",
doi = "10.1182/blood-2017-05-782102",
language = "English",
volume = "130",
pages = "2664--2677",
journal = "BLOOD",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "24",

}

RIS

TY - JOUR

T1 - Cytoprotective activated protein C averts Nlrp3 inflammasome induced ischemia reperfusion injury via mTORC1 inhibition

AU - Nazir, Sumra

AU - Gadi, Ihsan

AU - Al-Dabet, Moh'd Mohanad

AU - Elwakiel, Ahmed

AU - Kohli, Shrey

AU - Ghosh, Sanchita

AU - Manoharan, Jayakumar

AU - Ranjan, Satish

AU - Bock, Fabian

AU - Braun-Dullaeus, Ruediger C

AU - Esmon, Charles T

AU - Huber, Tobias B

AU - Camerer, Eric

AU - Dockendorff, Chris

AU - Griffin, John H

AU - Isermann, Berend

AU - Shahzad, Khurrum

N1 - Copyright © 2017 American Society of Hematology.

PY - 2017/12/14

Y1 - 2017/12/14

N2 - Cytoprotection by activated protein C (aPC) following ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation and hence conceptually cell-death forms disjunct from immunologically silent apoptosis are more likely to be relevant. As pyroptosis, cell death resulting from inflammasome activation, is typically observed in IRI we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRI. aPC treatment before or after myocardial IRI reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that Nlrp3 inflammasome activation preceded myocardial injury and apoptosis, corroborating a pathogenic role of the Nlrp3 inflammasome. The constitutively active Nlrp3(A350V) mutant abolished aPC's protective effect, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation in macrophages, cardiomyocytes, and cardiac fibroblasts via PAR-1 and mTORC1 signaling. Accordingly, inhibiting PAR-1 signaling, but not aPC's anticoagulant properties, abolished aPC's ability to restrict Nlrp3 inflammasome activity and tissue damage in myocardial IRI. Targeting biased PAR-1 signaling via parmodulin-2 restricted mTORC1 and Nlrp3 inflammasome activation and limited myocardial IRI as efficient as aPC. The relevance of aPC-mediated Nlrp3 inflammasome suppression following IRI was corroborated in renal IRI, where aPC's tissue protective effect was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1 dependent inflammasome activation and that mimicking biased aPC-PAR1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI.

AB - Cytoprotection by activated protein C (aPC) following ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation and hence conceptually cell-death forms disjunct from immunologically silent apoptosis are more likely to be relevant. As pyroptosis, cell death resulting from inflammasome activation, is typically observed in IRI we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRI. aPC treatment before or after myocardial IRI reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that Nlrp3 inflammasome activation preceded myocardial injury and apoptosis, corroborating a pathogenic role of the Nlrp3 inflammasome. The constitutively active Nlrp3(A350V) mutant abolished aPC's protective effect, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation in macrophages, cardiomyocytes, and cardiac fibroblasts via PAR-1 and mTORC1 signaling. Accordingly, inhibiting PAR-1 signaling, but not aPC's anticoagulant properties, abolished aPC's ability to restrict Nlrp3 inflammasome activity and tissue damage in myocardial IRI. Targeting biased PAR-1 signaling via parmodulin-2 restricted mTORC1 and Nlrp3 inflammasome activation and limited myocardial IRI as efficient as aPC. The relevance of aPC-mediated Nlrp3 inflammasome suppression following IRI was corroborated in renal IRI, where aPC's tissue protective effect was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1 dependent inflammasome activation and that mimicking biased aPC-PAR1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI.

KW - Journal Article

U2 - 10.1182/blood-2017-05-782102

DO - 10.1182/blood-2017-05-782102

M3 - SCORING: Journal article

C2 - 28882883

VL - 130

SP - 2664

EP - 2677

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 24

ER -