Phagocytic functions of neutrophils and macrophages are essential for immunity to microbial infection, but can also contribute to tissue injury during inflammatory responses and autoimmune pathologies. The overall goal of this application is to continue to extend our understanding of the molecular basis of phagocyte cytotoxicity focusing on two major opsonic receptors on phagocytes, Fc?Rs (receptors for IgG immune complex) and the ?2 integrin Mac-1 (receptor for complement fragment iC3b). Major accomplishments of the past 4 years were to 1) demonstrate that Vav proteins, exchange factor for Rho GTPase family members are required for several Mac-1 and Fc?R mediated adhesive functions in neutrophils, 2) identify Vav proteins as the major signal transducers of NADPH oxidase activation following Fc?R engagement, through regulation of Rac GTPases and phosphorylation of the NADPH oxidase p40phox, 3) present in vivo evidence that neutrophil Fc?R dependent but not complement dependent tissue injury requires Vav and Rac proteins, 4) define a role for Mac-1 in triggering neutrophil elastase release and subsequent hemorrhagic vasculitis in vivo, through activation of the src and syk kinases, and 5) demonstrate a critical role for Mac-1 on neutrophils in two additional complement dependent models, bullous pemphigoid and thrombotic glomerulonephritis. The current application builds on these discoveries. The objective of Aim I is to delineate mechanisms of neutrophil phagocytosis that are relevant for complement C3 mediated tissue injury and host defense. In particular we will examine both signals that lead to Mac-1 binding of its target and those that link Mac-1 to downstream effector functions.
In Aim II, we will further delineate mechanisms of Vav mediated regulation of the NADPH oxidase following Fc?R engagement in neutrophils and macrophages. We will also clarify the role of Vav and Rac in IgG or complement mediated phagocytosis in macrophages in models of autoimmune hemolytic anemia. We anticipate that the completion of our aims should lead to a better understanding of signaling pathways that link opsonic receptors to specific phagocyte cytotoxic functions. This may aid in the design of therapeutics to selectively target pathways responsible for tissue damage in inflammatory and autoimmune disorders while minimizing effects on host defense.

Public Health Relevance

The objective of this proposal is to understand the neutrophil dependent mechanisms that mediate injury to the dermal microvasculature, a well-recognized target of autoimmune damage that contributes to end organ/skin disease. For example, the inflammatory destruction of the vessel wall, vasculitis, is observed in autoimmune rheumatic diseases with cutaneous involvement being the most common, and neutrophil accumulation being a common feature. Drugs such as natalizumab, which interferes with neutrophil trafficking have demonstrated marked therapeutic efficacy in autoimmune diseases, but also exhibited potentially fatal immunosuppression. In this application we propose to delineate signaling pathways that potentially promote microvascular tissue damage, but are not required for neutrophil recruitment. This could lead to the identification of targeted therapeutic strategies that attenuate organ injury while minimally immunocompromising the host.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Mancini, Marie
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Brigham and Women's Hospital
United States
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Ganesan, Sandhya; Rathinam, Vijay A K; Bossaller, Lukas et al. (2014) Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1? production in response to ?-glucans and the fungal pathogen, Candida albicans. J Immunol 193:2519-2530
Mayadas, Tanya N; Cullere, Xavier; Lowell, Clifford A (2014) The multifaceted functions of neutrophils. Annu Rev Pathol 9:181-218
Rosetti, Florencia; Tsuboi, Naotake; Chen, Kan et al. (2012) Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency. J Immunol 189:3714-23
Chen, Kan; Nishi, Hiroshi; Travers, Richard et al. (2012) Endocytosis of soluble immune complexes leads to their clearance by FcýýRIIIB but induces neutrophil extracellular traps via FcýýRIIA in vivo. Blood 120:4421-31
Fu, Hongjun; Liu, Bin; Frost, Jeffrey L et al. (2012) Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar A? by microglia. Glia 60:993-1003
Tsuboi, Naotake; Ernandez, Thomas; Li, Xun et al. (2011) Regulation of human neutrophil Fc? receptor IIa by C5a receptor promotes inflammatory arthritis in mice. Arthritis Rheum 63:467-78
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
Mayadas, Tanya N; Rosetti, Florencia; Ernandez, Thomas et al. (2010) Neutrophils: game changers in glomerulonephritis? Trends Mol Med 16:368-78
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

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