Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke

David Yang Wei Fann, Yun An Lim, Yi Lin Cheng, Ker Zhing Lok, Prasad Chunduri, Sang Ha Baik, Grant R. Drummond, S. Thameem Dheen, Christopher G. Sobey, Dong Gyu Jo, Christopher Li Hsian Chen, Thiruma V. Arumugam

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Multi-protein complexes, termed “inflammasomes,” are known to contribute to neuronal cell death and brain injury following ischemic stroke. Ischemic stroke increases the expression and activation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) Pyrin domain containing 1 and 3 (NLRP1 and NLRP3) inflammasome proteins and both interleukin (IL)-1β and IL-18 in neurons. In this study, we provide evidence that activation of either the NF-κB and MAPK signaling pathways was partly responsible for inducing the expression and activation of NLRP1 and NLRP3 inflammasome proteins and that these effects can be attenuated using pharmacological inhibitors of these two pathways in neurons and brain tissue under in vitro and in vivo ischemic conditions, respectively. Moreover, these findings provided supporting evidence that treatment with intravenous immunoglobulin (IVIg) preparation can reduce activation of the NF-κB and MAPK signaling pathways resulting in decreased expression and activation of NLRP1 and NLRP3 inflammasomes, as well as increasing expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL, in primary cortical neurons and/or cerebral tissue under in vitro and in vivo ischemic conditions. In summary, these results provide compelling evidence that both the NF-κB and MAPK signaling pathways play a pivotal role in regulating the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons and brain tissue under ischemic conditions. In addition, treatment with IVIg preparation decreased the activation of the NF-κB and MAPK signaling pathways, and thus attenuated the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons under ischemic conditions. Hence, these findings suggest that therapeutic interventions that target inflammasome activation in neurons may provide new opportunities in the future treatment of ischemic stroke.

Original languageEnglish
Pages (from-to)1082-1096
Number of pages15
JournalMolecular Neurobiology
Volume55
Issue number2
DOIs
Publication statusPublished - Feb 2018

Keywords

  • Inflammasome
  • Mitogen-activated protein kinases
  • Neuronal cell death
  • NLRP
  • Nuclear factor kappa B
  • Stroke

Cite this

Fann, D. Y. W., Lim, Y. A., Cheng, Y. L., Lok, K. Z., Chunduri, P., Baik, S. H., ... Arumugam, T. V. (2018). Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke. Molecular Neurobiology, 55(2), 1082-1096. https://doi.org/10.1007/s12035-017-0394-9
Fann, David Yang Wei ; Lim, Yun An ; Cheng, Yi Lin ; Lok, Ker Zhing ; Chunduri, Prasad ; Baik, Sang Ha ; Drummond, Grant R. ; Dheen, S. Thameem ; Sobey, Christopher G. ; Jo, Dong Gyu ; Chen, Christopher Li Hsian ; Arumugam, Thiruma V. / Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke. In: Molecular Neurobiology. 2018 ; Vol. 55, No. 2. pp. 1082-1096.
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abstract = "Multi-protein complexes, termed “inflammasomes,” are known to contribute to neuronal cell death and brain injury following ischemic stroke. Ischemic stroke increases the expression and activation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) Pyrin domain containing 1 and 3 (NLRP1 and NLRP3) inflammasome proteins and both interleukin (IL)-1β and IL-18 in neurons. In this study, we provide evidence that activation of either the NF-κB and MAPK signaling pathways was partly responsible for inducing the expression and activation of NLRP1 and NLRP3 inflammasome proteins and that these effects can be attenuated using pharmacological inhibitors of these two pathways in neurons and brain tissue under in vitro and in vivo ischemic conditions, respectively. Moreover, these findings provided supporting evidence that treatment with intravenous immunoglobulin (IVIg) preparation can reduce activation of the NF-κB and MAPK signaling pathways resulting in decreased expression and activation of NLRP1 and NLRP3 inflammasomes, as well as increasing expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL, in primary cortical neurons and/or cerebral tissue under in vitro and in vivo ischemic conditions. In summary, these results provide compelling evidence that both the NF-κB and MAPK signaling pathways play a pivotal role in regulating the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons and brain tissue under ischemic conditions. In addition, treatment with IVIg preparation decreased the activation of the NF-κB and MAPK signaling pathways, and thus attenuated the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons under ischemic conditions. Hence, these findings suggest that therapeutic interventions that target inflammasome activation in neurons may provide new opportunities in the future treatment of ischemic stroke.",
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author = "Fann, {David Yang Wei} and Lim, {Yun An} and Cheng, {Yi Lin} and Lok, {Ker Zhing} and Prasad Chunduri and Baik, {Sang Ha} and Drummond, {Grant R.} and Dheen, {S. Thameem} and Sobey, {Christopher G.} and Jo, {Dong Gyu} and Chen, {Christopher Li Hsian} and Arumugam, {Thiruma V.}",
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Fann, DYW, Lim, YA, Cheng, YL, Lok, KZ, Chunduri, P, Baik, SH, Drummond, GR, Dheen, ST, Sobey, CG, Jo, DG, Chen, CLH & Arumugam, TV 2018, 'Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke', Molecular Neurobiology, vol. 55, no. 2, pp. 1082-1096. https://doi.org/10.1007/s12035-017-0394-9

Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke. / Fann, David Yang Wei; Lim, Yun An; Cheng, Yi Lin; Lok, Ker Zhing; Chunduri, Prasad; Baik, Sang Ha; Drummond, Grant R.; Dheen, S. Thameem; Sobey, Christopher G.; Jo, Dong Gyu; Chen, Christopher Li Hsian; Arumugam, Thiruma V.

In: Molecular Neurobiology, Vol. 55, No. 2, 02.2018, p. 1082-1096.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Fann, David Yang Wei

AU - Lim, Yun An

AU - Cheng, Yi Lin

AU - Lok, Ker Zhing

AU - Chunduri, Prasad

AU - Baik, Sang Ha

AU - Drummond, Grant R.

AU - Dheen, S. Thameem

AU - Sobey, Christopher G.

AU - Jo, Dong Gyu

AU - Chen, Christopher Li Hsian

AU - Arumugam, Thiruma V.

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N2 - Multi-protein complexes, termed “inflammasomes,” are known to contribute to neuronal cell death and brain injury following ischemic stroke. Ischemic stroke increases the expression and activation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) Pyrin domain containing 1 and 3 (NLRP1 and NLRP3) inflammasome proteins and both interleukin (IL)-1β and IL-18 in neurons. In this study, we provide evidence that activation of either the NF-κB and MAPK signaling pathways was partly responsible for inducing the expression and activation of NLRP1 and NLRP3 inflammasome proteins and that these effects can be attenuated using pharmacological inhibitors of these two pathways in neurons and brain tissue under in vitro and in vivo ischemic conditions, respectively. Moreover, these findings provided supporting evidence that treatment with intravenous immunoglobulin (IVIg) preparation can reduce activation of the NF-κB and MAPK signaling pathways resulting in decreased expression and activation of NLRP1 and NLRP3 inflammasomes, as well as increasing expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL, in primary cortical neurons and/or cerebral tissue under in vitro and in vivo ischemic conditions. In summary, these results provide compelling evidence that both the NF-κB and MAPK signaling pathways play a pivotal role in regulating the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons and brain tissue under ischemic conditions. In addition, treatment with IVIg preparation decreased the activation of the NF-κB and MAPK signaling pathways, and thus attenuated the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons under ischemic conditions. Hence, these findings suggest that therapeutic interventions that target inflammasome activation in neurons may provide new opportunities in the future treatment of ischemic stroke.

AB - Multi-protein complexes, termed “inflammasomes,” are known to contribute to neuronal cell death and brain injury following ischemic stroke. Ischemic stroke increases the expression and activation of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) Pyrin domain containing 1 and 3 (NLRP1 and NLRP3) inflammasome proteins and both interleukin (IL)-1β and IL-18 in neurons. In this study, we provide evidence that activation of either the NF-κB and MAPK signaling pathways was partly responsible for inducing the expression and activation of NLRP1 and NLRP3 inflammasome proteins and that these effects can be attenuated using pharmacological inhibitors of these two pathways in neurons and brain tissue under in vitro and in vivo ischemic conditions, respectively. Moreover, these findings provided supporting evidence that treatment with intravenous immunoglobulin (IVIg) preparation can reduce activation of the NF-κB and MAPK signaling pathways resulting in decreased expression and activation of NLRP1 and NLRP3 inflammasomes, as well as increasing expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL, in primary cortical neurons and/or cerebral tissue under in vitro and in vivo ischemic conditions. In summary, these results provide compelling evidence that both the NF-κB and MAPK signaling pathways play a pivotal role in regulating the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons and brain tissue under ischemic conditions. In addition, treatment with IVIg preparation decreased the activation of the NF-κB and MAPK signaling pathways, and thus attenuated the expression and activation of NLRP1 and NLRP3 inflammasomes in primary cortical neurons under ischemic conditions. Hence, these findings suggest that therapeutic interventions that target inflammasome activation in neurons may provide new opportunities in the future treatment of ischemic stroke.

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