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The Cellular and Molecular Mechanisms of ASC-dependent Inflammasomes in Neuroinflammation

Martin, Bradley N
http://rave.ohiolink.edu/etdc/view?acc_num=case1459420965

Abstract Details

, Doctor of Philosophy, Case Western Reserve University, Pathology.
The inflammasomes are multiprotein complexes that activate inflammatory caspases in response to infections and stress, resulting in the secretion of the pro-inflammatory cytokines IL-1ß and IL-18. The NLRP3 inflammasome is the most widely studied inflammasome complex, and is activated by structurally diverse stimuli, including both danger-associated and pathogen-derived molecules. ASC is an essential adaptor for NLRP3 activation, and is required for the activation of caspase-1 and/or caspase-8 following NLRP3 activation and nucleation, as well as for resultant cytokine production. Here, we found that the IkB kinase IKKa has a surprising and indispensable function as a negative regulator of ASC-containing inflammasomes. Seeking to understand how LPS-induced inflammasome priming redirects the ASC/ IKKa complex to the cytoplasm to permit inflammasome formation, we identified a TLR4-induced IRAK1/2-IKKi axis that directly promotes translocation of ASC/ IKKa to the cytoplasm, where ASC remains under the control of IKKa kinase activity until signal 2 of inflammasome activation is delivered. Notably, we observed that the promiscuous protein phosphatase PP2A was recruited to the ASC/ IKKa complex in response to extracellular ATP (signal 2). ATP-induced PP2A dephosphorylated IKKa and inhibited the kinase activity of IKKa, releasing ASC from the inhibitory complex and permitting participation in NLRP3 inflamamsome formation. We additionally identified a novel and surprising role for the ASC/NLRP3 inflammasome in CD4+ T cells during the development of experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. We observed that conditional deletion of ASC in T cell populations rendered mice resistant to Th17- but not Th1-mediated EAE. We further found that Th17 cells express the inflammasome components ASC, NLRP3, and pro-IL-1ß, and respond to extracellular ATP by secreting mature IL-1ß in a manner dependent on ASC, NLRP3, and caspase-8. Detailed analysis of Th17 cells in the periphery and CNS revealed that IL-1R expression is highly expressed on Th17 cells, but not Th1 cells. Utilization of RAG-/- mice reconstituted with IL-1ß/IL-18 deficient CD4+ T cells revealed that T cell-derived IL-1ß promotes Th17 cell survival and cytokine expression in the CNS. Together, these findings reveal a novel non-canonical T cell intrinsic inflammasome that is indispensable for Th17-mediated EAE pathogenesis.
George Dubyak (Committee Chair)
Clifford Harding (Committee Member)
Alex Huang (Committee Member)
Clive Hamlin (Committee Member)
Xiaoxia Li (Advisor)
Immunology

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Citations

  • Martin, B. N. (n.d.). The Cellular and Molecular Mechanisms of ASC-dependent Inflammasomes in Neuroinflammation [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1459420965

    APA Style (7th edition)

  • Martin, Bradley. The Cellular and Molecular Mechanisms of ASC-dependent Inflammasomes in Neuroinflammation. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1459420965.

    MLA Style (8th edition)

  • Martin, Bradley. "The Cellular and Molecular Mechanisms of ASC-dependent Inflammasomes in Neuroinflammation." Doctoral dissertation, Case Western Reserve University. Accessed MAY 14, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1459420965

    Chicago Manual of Style (17th edition)

case1459420965
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.