The incidence of atherosclerosis and type 2diabetes continues to increase world-wide, and the development of new therapeutics for metabolic disease is crucial. Notably, both diseases are associated with low grade systemic inflammation characterized by increased expression of cytokines, particularly interleukin-1b. Although chronic stimulation of the innate immune system by endogenous ligands is believed to underlie these metabolic diseases, the molecular mechanisms of activation remain unclear. The Nod-like receptor (NLR) family of innate immune sensors, such as the NLRP3 inflammasome, recognize certain danger signals leading to caspase-1 activation and processing and secretion of IL-1 family cytokines. This pathway is highly regulated and requires a two-hit model of inflammasome """"""""priming"""""""" and """"""""activation"""""""", but how endogenous ligands trigger these two steps is not clear. The scavenger receptor CD36 been implicated in the pathogenesis of atherosclerosis and diabetes, and binds a variety of modified endogenous ligands that accumulate in these diseases, including oxidized LDL (oxLDL), saturated fatty acids, islet amyloid polypeptide (IAPP). Notably, several of these ligands have recently been shown to be trigger the inflammasome and we hypothesize that engagement of CD36 may be a common mechanism by which this cytosolic complex senses metabolic-associated danger signals and leads to immune dysfunction. In this grant, we propose to (a) determine the role of cooperative signaling via CD36 and Toll-like receptors (TLRs) in """"""""priming"""""""" the inflammasome (step 1) in response to endogenous ligands, (b) determine how engagement of CD36 contributes directly to """"""""activation"""""""" of the inflammasome (step 2) through endolysosomal dysfunction and production of reactive oxygen species, and (c) test whether inhibition of CD36 in vivo blocks inflammasome activation and IL-1b production in mouse models of atherosclerosis and insulin resistance/diabetes. These studies will provide insight into the mechanisms by which the inflammasome is triggered during atherosclerosis and diabetes, and assess the potential of CD36 as a therapeutic target in the treatment of the chronic inflammation that characterizes these metabolic diseases. !
Atherosclerosis and type 2 diabetes are major contributors to morbidity and mortality worldwide, and these metabolic diseases continue to increase. Notably, both diseases are associated with low grade systemic inflammation characterized by increased expression of cytokines, particularly interleukin-1b. This proposal seeks to understand the mechanisms by which modified endogenous ligands induce chronic stimulation of the innate immune system in these metabolic diseases. !
|Okuda, Kendi; Tong, Mei; Dempsey, Brian et al. (2016) Leishmania amazonensis Engages CD36 to Drive Parasitophorous Vacuole Maturation. PLoS Pathog 12:e1005669|
|Savic, Daniel; Ramaker, Ryne C; Roberts, Brian S et al. (2016) Distinct gene regulatory programs define the inhibitory effects of liver X receptors and PPARG on cancer cell proliferation. Genome Med 8:74|
|Shrestha, Elina; Hussein, Maryem A; Savas, Jeffery N et al. (2016) Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages. J Biol Chem 291:11172-84|
|Moore, Kathryn J; Goldberg, Ira J (2016) Emerging Roles of PCSK9: More Than a One-Trick Pony. Arterioscler Thromb Vasc Biol 36:211-2|
|Vengrenyuk, Yuliya; Nishi, Hitoo; Long, Xiaochun et al. (2015) Cholesterol loading reprograms the microRNA-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler Thromb Vasc Biol 35:535-46|
|Pownall, Henry; Moore, Kathryn (2014) Commentary on fatty acid wars: the diffusionists versus the translocatists. Arterioscler Thromb Vasc Biol 34:e8-9|
|Moore, Kathryn J; Fisher, Edward A (2014) High-density lipoproteins put out the fire. Cell Metab 19:175-6|
|Moore, Kathryn J; Sheedy, Frederick J; Fisher, Edward A (2013) Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 13:709-21|
|Sheedy, Frederick J; Grebe, Alena; Rayner, Katey J et al. (2013) CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol 14:812-20|