Rac2 in integrin macrophage function

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Preliminary data from our laboratory has established a marked defect in alphavbeta3 and alpha4beta1 integrin directed migration of macrophages of vitronectin in the Rac2-/- mice. The alphavbeta3 and alpha4beta1 integrins mediate important components of inflammation. Macrophages must use the alphav integrins to migrate to sites of inflammation where they modulate inflammation and angiogenesis. Moreover the alphav integrins non-covalently associated with matrix degrading enzymes, MMPs and plasminogen activating systems to digest and remodel the extracellular matrix a necessary component of wound healing, inflammation and angiogenesis. Recent evidence has implicated the alphavbeta3 integrin as an important component of autoimmune arthritis and agents which block alphavbeta3 (function blocking monoclonal antibodies, LM609 and/or RGD peptides) can ameliorate the arthritic state. Both inflammation and angiogenesis are critical components of the pathogenesis of autoimmune arthritis. We propose in Aim 1 to examine the effect of Rac2 on alphavbeta3 and alpha4beta1 integrin signaling and migration in macrophages and non-hematopoietic cells in an effort to examine the specificity of Rac2 signaling in blood cells. We will examine blood specific upstream effectors of integrin signaling as possible components of a Rac2-dependent integrin-induced signaling complex in macrophages. In Aim 2 we will generate a Rac2 deficient collagen-induced arthritis model in DBA/1 mice to evaluate the contribution of Rac2 to autoimmunity mediated through control of inflammation and angiogenesis. These combined studies will potentially identify novel targets for development of anti-inflammatory agents for the treatment of arthritis and other autoimmune diseases.