Abstract 2382 Role of the NLRP3 inflammasome in fibrosis

Each year, over 40,000 children and adults die in the United States die from fibrosis. A main contributor to this disease is the NOD-, leucine-rich repeat (LRR), and pyrin domain (PYD) containing protein 3 known as the NLRP3 inflammasome. It is a cytosolic protein complex that activates and triggers an immune response when it receives certain danger signals such as uric acid and extracellular ATP or detects products from damaged cells. Before it is activated, the NLRP3 protein lies dormant in the cytosol, but when it detects danger signals or signals derived from damaged cells, its expression is increased, and it assembles with the adaptor protein called the apoptosis-associated speck-like protein containing a CARD (ASC), and with the effector protein procaspase-1. It is now the active NLRP3 inflammasome. This creates a large protein complex that positions two procaspase-1 proteins together where they autocatalytically cleave each other into active caspase-1. Once activated caspase-1 can then induce the maturation and secretion of a number of pro-inflammatory cytokines, the two most important being IL-1β and IL-18. These cytokines induce inflammation which aids in the clearance of pathogens or damaged cells. The exact nature of how the NLRP3 inflammasome is activated is not yet clearly known. Due to the NLRP3 inflammasome's large role in inflammation, it is found in inflammatory cells such as macrophages, dendritic cells, and lymphocytes, and in stromal cells such as epithelial cells, endothelial cells, and fibroblasts. Activation of the NLRP3 inflammasome has been strongly associated with fibrosis, which occurs when collagen and other extracellular matrix components build up in the tissues. This creates a hardened scar layer and occurs in response to the chronic activation of IL-1β or IL-18 by the NLRP3 inflammasome. The hardened scar layer disrupts the function of the organs, and depending on the affected organ, this can lead to death. Our protein modeling team, with support from 3-D Molecular designs, modeled the NLRP3 protein, one of the three main proteins that make up the NLRP3 inflammasome and investigated the inflammasome's role in the development of fibrosis as well as current treatments for the disease. Scientists are developing therapeutics that inactivate the NLRP3 inflammasome with the goal of either slowing collagen deposition to prevent fibrosis or finding a cure.