Cytoplasmic Lipid Bodies of Inflammatory Cells

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DESCRIPTION (provided by applicant): Lipid bodies are cytoplasmic inclusions that develop in leukocytes, including eosinophils and mast cells, associated with allergic inflammation. Our investigations of the formation and function of leukocyte lipid bodies have revealed that they are distinct, inducible endoplasmic reticulum (ER)-derived, membrane- and ribosome-containing organelles with diverse functional roles in inflammatory responses of leukocytes pertinent to allergic inflammation. Leukocyte lipid bodies contain all enzymes required for synthesizing cyclooxygenase (COX)- and lipoxygenase (LO)-derived eicosanoids. Lipid body formation, rapidly inducible in vitro and in vivo by specific intracellular signaling pathways, enhances leukocyte formation of COX- and LO-derived eicosanoids. Lipid bodies are discrete sites of new eicosanoid synthesis, as documented for immunolocalized LTC4, LTB4 and PGE2. Lipid body-derived eicosanoids function as both paracrine and intracrine mediators of allergic inflammation. Based on combined proteomic and ultrastructural studies, leukocyte lipid bodies are complex organelles with internal membranes and ribosomes whose proteome includes proteins involved in protein synthesis. In IgE-activated cells, lipid bodies are early sites of agonist- elicited 5-LO mRNA localization and de novo 5-LO, LTC4 synthase and cytosolic phospholipase A2 protein synthesis. In addition, lipid bodies are sites of localization of cytokines, including TNF- demonstrable in vivo in tissue and blood leukocytes, although mechanisms and consequences of lipid body cytokine local- ization are unknown. Our central hypothesis is that leukocyte lipid bodies associated with allergic inflammation are inducible organelles that have major roles in the regulated formation of eicosanoids and cytokines that function as intra- and extracellular mediators of allergic inflammation. Our investigations have three aims: 1) Investigate the formation and function of eicosanoids within lipid bodies by evaluating the regulation of eicosanoid- synthesizing enzymes at lipid bodies, including 5-LO regulatory interactions with other proteins in lipid bodies and lipid bodies as sites of differential eicosanoid formation. 2) Investigate the formation and function of cytokines within lipid bodies by studying mechanisms regulating the formation and accumulation of cytokines within leukocyte lipid bodies and whether lipid body localized cytokines function locally within lipid bodies by signaling via cytokine receptors present within lipid bodies. 3) Investigate the mechanisms regulating leukocyte lipid body-related mRNA expression and function. The planned studies aim to provide a better understanding of mechanisms by which leukocytes contribute to inflammation pertinent to allergic and other diseases. PUBLIC HEALTH RELEVANCE: Asthma and related disorders due to allergic inflammation are increasingly prevalent diseases. The research will help in understanding mechanisms of allergic inflammation that are responsible for making asthma and allergic diseases major public health problems.