Reconciliation of IL-1ß loss with TRIF-biased TLR4 signaling by monophosphate lipid A.

Toll-like receptor 4;Cell signaling;Inflammasome;Inflammation;Lipid A/LPS

Chelsea A. Embry

University:University of Louisville

Department:Microbiology and Immunology

关键词: Toll-like receptor 4;    Cell signaling;    Inflammasome;    Inflammation;    Lipid A/LPS;   

Others  :  https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=1404&context=etd

美国|英语

来源: The Universite of Louisville's Institutional Repository

【 摘 要 】

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 lowtoxicity; 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.