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.
Most inflammatory disorders of the lung (e.g. sepsis, acute lung injury, asthma, lung fibrosis and pneumonia) are affected by IL-1?, a hormone (or cytokine) that is produced by lung macrophages and central to inducing inflammation. We have new data to show that the release of IL-1? by macrophages occurs in discreet tiny packets called microvesicles. The work proposed will test how packaging of IL-1? into these vesicles occurs and how this packaging affects IL-1? responses in lung tissue. Results of this work will greatly impact our understanding of innate immune mechanisms and provide novel chances to treat lung inflammatory disorders.
|Ratner, Dmitry; Orning, M Pontus A; Proulx, Megan K et al. (2016) The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation. PLoS Pathog 12:e1006035|
|Hoyt, Laura R; Ather, Jennifer L; Randall, Matthew J et al. (2016) Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation. J Immunol 197:1322-34|
|Shamaa, Obada R; Mitra, Srabani; Gavrilin, Mikhail A et al. (2015) Monocyte Caspase-1 Is Released in a Stable, Active High Molecular Weight Complex Distinct from the Unstable Cell Lysate-Activated Caspase-1. PLoS One 10:e0142203|
|Sundaram, Kruthika; Mitra, Srabani; Gavrilin, Mikhail A et al. (2015) House Dust Mite Allergens and the Induction of Monocyte Interleukin 1? Production That Triggers an I?B?-Dependent Granulocyte Macrophage Colony-Stimulating Factor Release from Human Lung Epithelial Cells. Am J Respir Cell Mol Biol 53:400-11|
|Mitra, Srabani; Wewers, Mark D; Sarkar, Anasuya (2015) Mononuclear Phagocyte-Derived Microparticulate Caspase-1 Induces Pulmonary Vascular Endothelial Cell Injury. PLoS One 10:e0145607|
|Rahman, Mohd Akhlakur; Sundaram, Kruthika; Mitra, Srabani et al. (2014) Receptor interacting protein-2 plays a critical role in human lung epithelial cells survival in response to Fas-induced cell-death. PLoS One 9:e92731|
|Ghonime, Mohammed G; Shamaa, Obada R; Das, Srabani et al. (2014) Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J Immunol 192:3881-8|
|Liu, Ming-Jie; Bao, Shengying; Gálvez-Peralta, Marina et al. (2013) ZIP8 regulates host defense through zinc-mediated inhibition of NF-?B. Cell Rep 3:386-400|
|Gillette, Devyn D; Shah, Prexy A; Cremer, Thomas et al. (2013) Analysis of human bronchial epithelial cell proinflammatory response to Burkholderia cenocepacia infection: inability to secrete il-1?. J Biol Chem 288:3691-5|
|Ghonime, Mohammed G; Shamaa, Obada R; Eldomany, Ramadan A et al. (2012) Tyrosine phosphatase inhibition induces an ASC-dependent pyroptosis. Biochem Biophys Res Commun 425:384-9|
Showing the most recent 10 out of 23 publications