Keystone Symposia: Metabolic Control of Inflammation and Immunity
Venue: Beaver Run Resort
|Event Date/Time: Jan 21, 2013||End Date/Time: Jan 26, 2013|
|Early Registration Date: Nov 19, 2012|
IL-1b and IL-18 are potent proinflammatory cytokines that are synthesized as pro-forms and matured by the aspartate-specific cysteine protease, IL-1-converting enzyme (ICE or caspase-1). The caspase-1 activation platform, or inflammasome, contains one of a number of â€˜sensorâ€™ proteins that respond to a bewildering array of inflammatory insults: including the presence of intracellular pathogens, disruption of membrane integrity, and mitochondrial reactive oxygen species. Many of these sensors, but not all, are members of the NOD family of intracellular proteins. There are upwards of 30 such proteins encoded in the human genome. This molecular apparatus generates active caspase-1 responsible not only for the proteolytic maturation of IL-1b and IL-18, but also pyroptosis, a pro-inflammatory mode of cell death.
While, mutations in the NOD sensors have been associated with relatively rare periodic fever syndromes, there is newfound interest in them with the realization that one member (NOD2) is the most commonly mutated gene in inflammatory bowel disease (IBD). Further, there has been the recent insight that mutations in other IBD susceptibility genes, such as ATG16L, lead to activation of the inflammasome, possibly due to a deficit in autophagic efficiency and consequent increase in reactive oxygen species that trigger a NOD sensor. Superimposed on this exciting insight has been the understanding that the NOD sensors also respond to metabolic stress, the hallmark of disease states such as Type 2 diabetes. Inflammasome mediated inflammation, likely drives insulin resistance as suggested by a recent clinical trial where neutralizing IL-1b led to a decrease in systemic markers of inflammation and improved glycemic control.
Other recently emergent data concerns the interplay of metabolism and the innate and adaptive immune responses. Together, these have dramatically underscored the importance of the inflammation and immunity in metabolic disease states.