Date on Master's Thesis/Doctoral Dissertation
Microbiology and Immunology
Mitchell, Thomas C.
Toll-like receptor 4; Cell signaling; Inflammasome; Inflammation; Lipid A/LPS
Lipids; Anti-inflammatory agents
Monophosphoryl Lipid A (MPLA), a derivative of LPS endotoxin, is a TLR4 agonist that displays as little as 0.1-1% as much toxicity as its parent molecule while retaining immunostimulatory properties. We discovered that MPLA activates a TRIF-biased pattern of TLR4 signaling, resulting in reduced production of MyD88-dependent pro-inflammatory factors, and credited TRIF-bias for MPLA's reduced toxicity. A contemporary study showed that MPLA fails to promote maturation of the potent inflammatory cytokine IL-1ß. This dissertation seeks to reconcile MPLA's TRIF-biased signaling with IL-1 ß loss, and to determine the ultimate cause of MPLA's reduced toxicity compared to LPS. We find that TRIF-biased TLR4 activation results in weak MyD88-dependent induction of NLRP3, a critical inflammasome component required for IL-1 ß production. MPLA's loss of IL-1 ß results in decreased potentiation of MyD88-dependent inflammatory factors in vivo and reduced IL-1 RI-dependent hepatotoxicity. Ultimately, TRIF-biased TLR4 signaling is the causative factor resulting in MPLA's immunogenicity with low toxicity; however more studies are needed to determine the initial events leading to the TRIF-dependent Signaling cascade. This dissertation describes the mechanisms responsible for MPLA's reduced induction of inflammatory responses and outlines how this signaling may be exploited for therapeutic use.
Embry, Chelsea A., "Reconciliation of IL-1ß loss with TRIF-biased TLR4 signaling by monophosphate lipid A." (2011). Electronic Theses and Dissertations. Paper 405.