Macrophage inflammasome regulation

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DESCRIPTION (provided by applicant): Innate immunity's importance in lung defense against external challenges has been heightened by the recent discovery of distinct intracellular pathogen recognition receptors that detect danger signals that gain access to the cytosol of macrophages. These receptors include NOD-like receptors (NLRs) as well as NOD independent sensors such as pyrin. A critical function of the intracellular sensors is to regulate the enzyme caspase-1 through an inflammasome complex. In an inflammasome, NLRs and NOD-independent sensors interact, via pyrin domains (PYD) or caspase recruitment domains (CARD), with an adaptor protein, ASC, to induce caspase-1 dimerization and autoactivation. Caspase-1 then cleaves and activates the precursors of IL-1¿ and IL-18, molecules that have been strongly associated with asthma, ARDS, pneumonia and pulmonary fibrosis. However, despite this conceptual advance, it remains obscure how this inflammasome complex is physically linked to IL-1¿ processing and release, limiting our understanding of lung inflammation and our ability to create new therapies. In this context, the present application seeks to expand upon the inflammasome hypothesis by linking its structure and function to the mechanisms that promote the release of the leaderless protein IL-1¿. We propose a novel structure, the releasosome. We hypothesize that this novel exosomal structure encapsulates proIL-1¿ together with inflammasome components in an actin filament regulated vesicle. Pyrin and ASC are known actin binding proteins. Thus, in this model, microvesicular IL-1¿ is presented to target cell membranes (e.g. lung fibroblasts or epithelium) in a highly concentrated packet where its secondary exocytosis can be controlled by target cell receptors that modulate local concentrations of ATP (a classical inflammasome activating factor). The project proposes to test the following specific hypotheses, 1) IL-1¿ release is predominantly from exosomes; 2) the target cell induced rupture of these exosomes provides a mechanism to focus IL-1¿ activity; 3) pyrin and ASC interactions modulate the exosomal packaging of caspase-1 for release; and 4) actin interactions with proIL-1¿ are critical to exosomal inflammasome proIL-1¿ interaction. If confirmed, these novel hypotheses will change our concepts about IL-1¿ regulation and provide new treatment options for inflammatory lung disorders.