Metabolic regulation of inflammatory processes: HIF-1alpha and IDO as anti-infectious effector molecules in professional phagocytes
Final Report Abstract
In this project we analyzed the influence of the oxygen regulated transcription factor hypoxia inducible factor (HIF)1α and the enzyme indoleamine 2,3-dioxygenase (IDO) on the function of dendritic cells (DC) in comparison to macrophages in the context of infection. We used DC- or macrophage-specific HIF1α-deficient mice to study the differentiation and function of these cell types under normoxic or hypoxic conditions in comparison to wild-type mice. We found that DC show a reduced survival but enhanced maturation under hypoxia in a HIF1α-independent manner. We also observed reduced proinflammatory cytokine production under hypoxia, but increased production of IL-22 and of the chemokines CCL17 and CCL22. Enhanced production of IL-22 under hypoxia was demonstrated to be HIF1α-dependent. In comparison, macrophages showed enhanced production of IL-12 and TNF under hypoxia in the absence of HIF1α but decreased production of IL-10. In both cell types altered chemokine receptor expression under hypoxia was HIF1α-dependent. Following either E. coli, S. aureus or listeria infection macrophages but not DC displayed a better survival under hypoxia and the presence of Hif1α slightly enhanced killing of E. coli in both cell types. As for the in vitro experiments, we did not see major differences in resistance of conditional HIF1α-deficient mice to infection with S. aureus or listeria in vivo. During the second part of the project we were able to successfully generate a new mouse mutant with inducible overexpression of IDO. In these mice the indo cDNA was inserted into the rosa26 locus following a loxP-flanked stop cassette. After breeding of this line to LysMcre mice we observed a strong increase in serum kynurenine levels up to 2 μg/ml, indicating a strongly enhanced IDO activity. Unexpectedly, r26IDOLysM Mice were found to be significantly more susceptible to LPS shock than wild-type controls.
Publications
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(2008) Decreased susceptibility of mice towards infection with Listeria monocytogenes in the absence of Interleukin-18. Infect Immun. 76: 3881-3890
Lochner M, Kastenmüller K, Neuenhahn M, Weighardt H, Busch DH, Reindl W, and Förster I
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(2009) Funktion des Chemokins CCL17 bei allergischen Immunreaktionen der Haut. Dissertation. Heinrich Heine University Düsseldorf
Stutte S
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(2010) Proinflammatory cytokines down-regulate intestinal selenoprotein P biosynthesis via NOS2 induction. Free Radic. Biol. Med. 49: 777-785
Speckmann B, Pinto A, Winter M, Förster I, Sies H, and Steinbrenner H
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(2010) Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells. Proc. Natl. Acad. Sci. USA 107: 8736-8741
Stutte S, Quast T, Gerbitzki N, Savinko T, Novak N, Reifenberger J, Homey B, Kolanus W, Alenius H, and Förster I
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(2011) Activation of the inflammasome by amorphous silica and TiO2 nanoparticles in murine dendritic cells. Nanotoxicology 5: 326-340
Winter M, Beer HD, Hornung V, Krämer U, Schins RPF, and Förster I
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(2012) Influence of hypoxia inducible factor 1α on dendritic cell differentiation and migration. Eur. J. Immunol. 42: 1226-1236
Köhler T, Reizis B, Johnson RS, Weighardt H, and Förster I
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(2012) Influence of hypoxia inducible factor 1α on dendritic cell differentiation and migration. Eur. J. Immunol. 42: 1226-1236
Köhler T, Reizis B, Johnson RS, Weighardt H, and Förster I
