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Title page for ETD etd-08022017-122352


Type of Document Dissertation
Author Rhoads, Jillian Patricia
URN etd-08022017-122352
Title Oxidized Low Density Lipoprotein Immune Complexes Prime the NLRP3 Inflammasome and Modulate T cell Responses in Atherosclerosis
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Daniel Moore Committee Chair
David Harrison Committee Member
Holly Algood Committee Member
Mark Boothby Committee Member
Keywords
  • IL-1b
  • dendritic cells
  • inflammasome
  • sterile inflammation
  • atherosclerosis
Date of Defense 2017-05-22
Availability unrestricted
Abstract
Oxidized low-density lipoprotein (oxLDL) is known to activate inflammatory responses in a variety of cells, especially macrophages and dendritic cells. Much of the oxLDL in circulation is complexed to antibodies, and these resulting immune complexes (ICs) are a prominent feature of chronic inflammatory diseases including atherosclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Levels of oxLDL-ICs often correlate with disease severity; however, it was previously unknown how oxLDL-ICs modulate immune responses. This work demonstrates that bone marrow-derived dendritic cells (BMDCs) incubated with oxLDL-ICs secrete significantly more IL-1β compared with BMDCs treated with free oxLDL, and treatment of BMDCs with oxLDL-ICs increased expression of inflammasome-related genes. This inflammasome priming was due to oxLDL-IC signaling via multiple receptors, and signaling through these receptors converged on the adaptor protein CARD9, a component of the CARD9-Bcl10-MALT1 complex. Injection of oxLDL-ICs into LDLr-/- mice enhanced atherosclerotic lesion size and caused aortic dissection which may promote lesion instability. Finally, oxLDL IC-mediated IL-1β production resulted in increased Th17 polarization and cytokine secretion. Collectively, these data show that oxLDL-ICs induce potent and unique innate and adaptive immune responses.
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