Role of Macrophage Arginase in Anti-Bacterial Immunity

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DESCRIPTION (PROVIDED BY APPLICANT): The tight control of macrophage function is central to inflammatory and immune responses. Arginase I (Arg I) is a newly recognized marker of activated macrophages. The profound induction of normally silent Arg I expression in response to infectious agents, in asthma and in other diseases involving chronic inflammation suggests that new insights into macrophage function in immunity can be uncovered by understanding the biology of Arg I, and the pathways that converge to regulate its expression. However, a major gap in understanding Arg I function in the context of immune responses is the translation of correlative expression data and in vitro findings to in vivo systems because Arg I also plays an irreplaceable role in liver function. To address this problem, mouse models were developed where Arg I is specifically deleted or over-expressed in macrophages. The preliminary data establish the fidelity of these models and set the stage for a detailed examination of Arg I function in immune responses to bacteria. Infection models will be studied because Arg I function is most directly implicated in two pathways that regulate immunity to bacteria: nitric oxide (NO) biosynthesis and the promotion of fibrosis. Four aims are proposed to study Arg I biology in macrophages. In Aim 1, the role of Arg I in regulating the biogenesis of NO will be studied using systems deficient in Arg I. In Aim 2, the role of Arg I in regulating inflammation, tissue repair and NO biosynthesis in septic shock models will be dissected. In Aim 3, the function of Arg I in regulating the immunological and pathological outcomes in tuberculosis, a chronic disease that is dependent on exquisite control of NO levels for effective immunity, will be investigated. In Aim 4, we will extend our current studies of Arg I regulation in macrophages to determine how pathogens themselves induce expression. The outcomes of the proposed studies will reveal new elements of Arg I function and provide rationale for approaching Arg I as a target in inflammatory diseases.