The broad goal of this application is to understand the biological function(s) of an enzyme termed secretory group V phospholipase A2 (sPLA2), particularly as it pertains to control of infections and pulmonary inflammation. Group V sPLA2 is prominently expressed in mast cells and macrophages, cells that are critical for sensing harmful organisms at their sites of entry into the body and in generating the acute inflammatory response that is essential for efficient clearing and killing of these pulmonary pathogens. Group V sPLA2 regulates the generation of leukotrienes and prostaglandins in both mast cells and macrophages in response to stimuli that are surrogates for invading pathogens, namely zymosan, derived from yeast cell walls, and agonists of toll-like receptor (TLR)-2. Our early studies indicate that the enzyme regulates phagocytosis and killing of the yeast Candida albicans in pulmonary macrophages and activation of signaling molecules called mitogen-activated protein kinases in response to TLR2 stimulation of mast cells.
The aims of this proposal are therefore to understand how group V sPLA2 regulates phagocytosis and killing of fungi; to understand how group V sPLA2 regulates TLR signaling in mast cells; and to determine the importance of the enzyme for generation of pulmonary inflammatory responses to invading microorganisms and their clearance from the host. To achieve these aims we will compare the generation of lipids and early signaling events following zymosan stimulation between macrophages that lack group V sPLA2 and normal macrophages. We will express normal and mutant forms of group V sPLA2 in macrophages to examine the relationship between the structure of the enzyme and its function. We will compare the generation of lipids and early signaling events in response to TLR2 stimulation between mast cells that lack group V sPLA2 and normal mast cells. We will study the subcellular location of group V sPLA2 in mast cells stimulated through TLR2. Finally, we will use mice that lack group V sPLA2 to study the relevance of these findings in models of fungal pulmonary infection. The lung is a major site of entry into the body for infectious organisms. The ability to mount an effective and appropriate inflammatory response to these organisms is essential for survival. The proposed studies will define the function of group V phospholipase A2 in host defense. They will provide new information on the function of this enzyme, which is presently poorly understood. These studies will provide new insight into the regulation of pulmonary inflammation and innate immunity. ? ? ?
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