A large number of studies indicate that environmental stimuli impact the pathogenesis of asthma both by triggering acute events and by molding the developing adaptive immune responses characteristic of this disease. Much of our study of the immune response of the asthmatic lung to innate stimuli such as endotoxin has focused on the role of the Toll receptors, cell surface molecules which through pattern recognition alert the cell in response to the presence of foreign agents. Recent studies by a number of labs, including that of our collaborator Dr. Ting, have identified a novel family of genes, initially termed CATERPILLER genes, which play a critical role in the response of cells to environmental insults. These genes encode cytoplasmic proteins characterized by pyrin, nuclear binding, and leucine-rich domains, similar to those found in Toll receptors. In response to various stimuli, a number of these proteins have been shown to assemble into complexes termed """"""""inflammasomes"""""""" which help to orchestrate the response of the cell to the environmental threat. In the case of complexes formed with three of the CATERPILLER genes, Nlrpl, cryopyrin/Mrp3, and Nlrc4/lpaf1, this response includes the production of cytokines and the initiation of events that lead to necrosis or apoptosis. Previous studies by our group have shown that ATP is required for the maturation and release of IL-1(3 from endotoxin primed mouse macrophages and, furthermore, that this is mediated by ATP activation of the ion channel, P2X7. A model has emerged in which activation of P2X7 leads to alteration in intracellular K+, which in turn leads to activation of some inflammasomes. More recently, it has been suggested that P2X7 recruits the hemichannel pannexin-1 and that this complex mediates the passage of bacterial molecules from the endosomal compartment to the host cytosol leading to inflammasome activation. The overall hypothesis of this application is that the activation of the P2X7/inflammosome pathway plays an important part in the response of cells to environmental stimuli, regulating both the maturation and release of the family of IL-1 cytokines and modulating the apoptotic response of the lung to these stimuli. This pathway, therefore, can contribute both to the pathogenesis of asthma as well as to disease exacerbations triggered by environmental stimuli.
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