Antibodies complexed with self-antigens and immune cell reactions to these immune complexes (ICs) are defining features of many autoimmune diseases. The long-term goal of our project is to define the receptors and intracellular signaling molecules that regulate neutrophil responses to ICs. Activating Fc? receptors (Fc?Rs) for IgG-ICs structurally differ in human and murine neutrophils. To understand the physiological function of the human receptors we generated mice expressing the uniquely human Fc?RIIA and Fc?RIIIB selectively on neutrophils of mice lacking their own activating Fc?Rs. Our analysis of these animals led to the identification of Fc?RIIA on neutrophils as the primary link between antibody and tissue injury, demonstrated new roles for Fc?RIIA and Fc?RIIIB in neutrophil slow rolling and adhesion to the vessel wall, and provided evidence in vivo that Fc?RIIA engagement triggers release of neutrophil extracellular traps (NETs) while Fc?RIIIB serves a novel role in IC uptake. The broad objective of the current application is to determine how Fc?RIIA's activity is regulated, which is poorly understood. We identified two negative regulators of Fc?RIIA. First, the integrin Mac-1 played an unanticipated inhibitory role in Fc?RIIA dependent lupus nephritis in a novel mouse model of the disease induced by the passive transfer of human systemic lupus erythematosus (SLE) sera. Mac-1 modulation of Fc?RIIA mediated neutrophil recruitment was a key step in preventing renal damage. This has implications in humans as neutrophils from individuals with the nonsynonymous Mac-1 R77H polymorphism associated with SLE susceptibility exhibited defects in neutrophil adhesion. Second, we identified inhibitors of Fc?RIIA mediated neutrophil function using a high throughput small molecule chemical screen. Interestingly, a number of them engaged G-protein coupled receptors (GPCRs) classically associated with neurotransmission in the nervous system. Together, our data have led to the hypothesis that the function of Fc?RIIA is dynamically regulated by heterologous surface receptors to balance and tailor the neutrophil's response to IgG ICs. This hypothesis will be tested in three aims. We propose to: 1) Identify the intracellular signaling complex assembled by Mac-1 to inhibit Fc?RIIA activity in response to ICs, 2) Delineate the underlying structural and functional consequences of the Mac-1 R77H variant, and 3) Understand how a neuronal related GPCR, targets Fc?RIIA signaling and its specificity for this pathway. These objectives will be achieved with a multidisciplinary approach that uses the tools of biochemistry and molecular biology in primary murine neutrophils and human neutrophil-like cell lines coupled with the analysis of genetically engineered mice in mouse models of disease. We anticipate that the new information provided by the proposed studies will increase our understanding of Fc?RIIA dependent mechanisms of IC-induced neutrophil activation and provide therapeutic leads for the prevention of organ damage in antibody-mediated inflammatory disorders.
Autoimmune diseases afflict 5-8% of the population; with a large percentage of these being triggered by pathogenic IgG. Currently; there are no preventive treatments or strategies aside from immunosuppression and treatment with IVIG. In mice; Fc Rs; receptors for IgG; have emerged as critical players in IC-induced injury of the lung; skin; and joints. The objective of this proposal is to understand how the activity of human Fc RIIA; a key inducer in IgG mediated cytotoxic responses; is regulated in neutrophils. We anticipate that this will lead to the identification of therapeutic strategies that avert target tissue injury in autoimmune disorders.
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|Li, Xun; Utomo, Ahmad; Cullere, Xavier et al. (2011) The ?-glucan receptor Dectin-1 activates the integrin Mac-1 in neutrophils via Vav protein signaling to promote Candida albicans clearance. Cell Host Microbe 10:603-15|
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|Hirahashi, Junichi; Hishikawa, Keiichi; Kaname, Shinya et al. (2009) Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury. Circulation 120:1255-65|
|Mayadas, Tanya N; Tsokos, George C; Tsuboi, Naotake (2009) Mechanisms of immune complex-mediated neutrophil recruitment and tissue injury. Circulation 120:2012-24|
|Cullere, Xavier; Lauterbach, Michael; Tsuboi, Naotake et al. (2008) Neutrophil-selective CD18 silencing using RNA interference in vivo. Blood 111:3591-8|
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