Chronic granulomatous disease (CGD) is a rare, inherited disorder of various defects of the NADPH oxidase rendering it dysfunctional and predisposing to invasive and life-threatening bacterial and fungal infection. While the role of the defective oxidase in immunodeficiency is undisputed, disordered inflammation in the disease (e.g., poor wound healing, obstructing granulomata and autoimmunity), which may or may not be associated with infection, remains unexplained. It is hypothesized that disordered inflammation in CGD results from defective phosphatidylserine (PS) exposure and accumulation on apoptosing CGD neutrophils that leads to impaired recognition and engulfment by phagocytes. Preliminary data suggest that the functioning NADPH oxidase is required for appropriate PS exposure during neutrophil apoptosis, an event that requires coordinate activation of phospholipid (PL) scrambling to expose PS, and inactivation of the aminophospholipid translocase which returns PS to the plasma membrane inner leaflet. This proposal seeks to define the defect in PS exposure on CGD neutrophils by assessing both PL scrambling and aminophospholipid translocase activity. It is hypothesized that apoptosing CGD neutrophils will have diminished PL scrambling and sustained aminophospholipid translocase activity. Exposure of PS on apoptotic cells is required for recognition by phagocytes and is mediated through a receptor, the PSR, that recognizes PS in a stereospeciflc manner. Engagement of the PSR along with other tethering receptors mediates the ingestion of apoptotic neutrophils by an immunologically """"""""silent"""""""" mechanism that results in TGFbeta production and suppression of pro-inflammatory cytokine production from the phagocyte. Thus, we hypothesized that PS deficient apoptotic CGD neutrophils will show impaired phagocytic recognition and engulfment, and promote pro-inflammatory cytokine production. Furthermore, unengulfed CGD neutrophils will undergo post-apoptotic cytolysls releasing injurious proteins. Both in vitro phagocytic engulfment assays and in vivo murine models are proposed. It is predicted that apoptotic CGD neutrophils, relative to apoptotic normal neutrophils, instilled into the inflamed peritonea of wild type mice will show delayed clearance, suppression of TGFbeta production and enhanced pro-inflammatory cytokine production; restoration of PS on the surface of CGD neutrophils will reverse this. Finally, injection of CGD mice with sterile fungal hyphae in the presence of PS liposomes will lead to enhanced clearance of accumulating neutrophils, enhanced TGFbeta production and resolution of inflammation. It is expected that data from this investigation will identify novel potential therapeutic targets to address disordered inflammation of CGD.
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