Metabolic regulation of inflammatory processes: HIF-1alpha and IDO as anti-infectious effector molecules in professional phagocytes

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Tissue inflammation is a hallmark of microbial infections and is characterized by a local reduction in oxygen levels due to enhanced cellular infiltration and vascular obstruction. The transcription factor Hypoxia-inducible factor (HIF)-1α mediates essential changes in gene expression, like the metabolic switch to the glycolytic pathway or induction of angiogenesis, to permit cellular adaptation to reduced oxygen supply. In addition, HIF-1α has direct anti-microbial functions, leading to the production of defensins, proteases and nitric oxide (NO). Besides stabilization of the HIF-1α protein, hypoxia also enhances the enzymatic activity of the tryptophan-degrading heme enzyme indoleamine 2,3-dioxygenase-1 (IDO), which has both anti-microbial and immunosuppressive effector functions. In contrast, HIF-1α may inhibit IDO activity through induction of NO. In this project, we want to study the functional importance and interplay of HIF-1α and IDO during inflammatory processes mediated by dendritic cells (DC) and macrophages. To this end, we have generated two mutant mouse lines with efficient cell-type specific ablation of HIF-1α in DC, using either CD11cCre or CCL17Cre mice. We have shown that DC maturation is enhanced under hypoxic culture conditions, whereas IL-12p70 production is impaired in a HIF-1α-independent manner. In contrast, hypoxia-induced upregulation of CD73 and chemokine receptors CXCR4 and CCR7 were found to be HIF-1α-dependent in DC. The effect of these alterations on chemokine-dependent migration of DC in vitro and in vivo will be subject to future investigation. We also generated ES cell lines, which allow for cell-type specific overexpression of IDO, using the Cre/loxP recombination system. Upon germline transmission of this mutation, we will be able to constitutively induce IDO in either CCL17+ DC or macrophages. HIF-1α-deficient-, IDO-deficient- (Project 4), or IDO-overexpressing mice will be challenged in different infection models, using systemic or local infection with Listeria monocytogenes, Staphylococcus aureus, Chlamydia pneumoniae and MCMV. In this way, we want to determine the contribution of HIF-1α and IDO to microbial defense and immune regulation.