Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum.
Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates metabolic and immune response genes in the setting of low oxygen tension and inflammation. We investigated the function of HIF-1α in the host response to Histoplasma capsulatum because granulomas induced by this pathogenic fungus develop hypoxic microenvironments during the early adaptive immune response. In this study, we demonstrated that myeloid HIF-1α-deficient mice exhibited elevated fungal burden during the innate immune response (prior to 7 d postinfection) as well as decreased survival in response to a sublethal inoculum of H. capsulatum The absence of myeloid HIF-1α did not alter immune cell recruitment to the lungs of infected animals but was associated with an elevation of the anti-inflammatory cytokine IL-10. Treatment with mAb to IL-10 restored protective immunity to the mutant mice. Macrophages (Mϕs) constituted most IL-10-producing cells. Deletion of HIF-1α in neutrophils or dendritic cells did not alter fungal burden, thus implicating Mϕs as the pivotal cell in host resistance. HIF-1α was stabilized in Mϕs following infection. Increased activity of the transcription factor CREB in HIF-1α-deficient Mϕs drove IL-10 production in response to H. capsulatum IL-10 inhibited Mϕ control of fungal growth in response to the activating cytokine IFN-γ. Thus, we identified a critical function for Mϕ HIF-1α in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1α and CREB is critical for activation of Mϕs by IFN-γ and effective handling of H. capsulatum.
Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45220;
Roger A
0000-0001-7565-7216
RA
Fecher
Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45220;
Michael C
MC
Horwath
Department of Infectious Diseases and Microbiology, University of Lübeck, 23538 Lübeck, Germany; and.
Dirk
0000-0001-8812-489X
D
Friedrich
Department of Infectious Diseases and Microbiology, University of Lübeck, 23538 Lübeck, Germany; and.
Jan
J
Rupp
Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Medical Service, Veterans Affairs Hospital, Cincinnati, OH 45220 george.deepe@uc.edu.
George S
0000-0001-6158-6461
GS
Deepe
D000818:Animals; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006658:Histoplasma / Q000276:immunology; D006660:Histoplasmosis / Q000276:immunology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D060888:Real-Time Polymerase Chain Reaction
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016753:Interleukin-10; D050882:CREB-Binding Protein