Interleukin-1 family members are key inflammatory cytokines in the innate immune response to infection. While IL-1 is necessary for proper defense against pathogens, the production of this cytokine must be carefully regulated in order to prevent immunopathology. One checkpoint on the release of IL-1 family cytokines is their requirement for post-translational processing by a multi-protein complex known as the inflammasome, which serves as a platform for recruiting and activating the protease caspase-1. Sensing of extracellular bacteria by Toll-like receptors (TLRs) triggers the transcription of il1b mRNA, but IL-1 is not released until inflammasome sensor proteins recognize bacterial products that have entered the cellular cytosolic compartment. Type I interferons (IFN-I) are known to inhibit inflammasome activity, which partially explains their long-recognized immunosuppressive capacity, although the underlying mechanisms have been unclear. Induction of the enzyme Ch25h, which produces 25-hydroxycholesterol (25-HC) from cholesterol, is a key component of IFN-I- mediated inhibition of inflammasomes. Ch25h is an IFN-I-stimulated gene in macrophages, and deletion of Ch25h results in increased capase-1 activity and release of IL-1. 25-HC is a potent suppressor of the Sterol Response Element Binding Protein (SREBP) cholesterol biosynthetic pathway, and Ch25h-deficient macrophages additionally display increased SREBP pathway activity after TLR stimulation. Deletion of SCAP, a protein required for SREBP activation, in macrophages results in decreased inflammasome activity. Based on these data, I aim to characterize how the SREBP pathway positively regulates inflammasomes. Specifically, I propose to determine the necessity and sufficiency of SREBP proteins in augmenting inflammasome function, and to define which step of inflammasome activation they regulate (Aim 1). I also propose to test the hypothesis that SREBPs promote inflammasome function via the production of cholesterol (Aim 2).
Millions of Americans suffer from inflammatory diseases, such as metabolic syndrome and atherosclerosis, which are associated with high cholesterol levels; however, how cholesterol promotes inflammation is poorly understood. We hope to understand how the cholesterol biosynthetic pathway influences the production of a key inflammatory mediator, IL-1, which will provide a first step in developing therapies for linked metabolic- inflammatory diseases.
| Lu, Erick; Dang, Eric V; McDonald, Jeffrey G et al. (2017) Distinct oxysterol requirements for positioning naïve and activated dendritic cells in the spleen. Sci Immunol 2: |
| Dang, Eric V; McDonald, Jeffrey G; Russell, David W et al. (2017) Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation. Cell 171:1057-1071.e11 |
