Inverse Correlation between IL-10 and HIF-1α in Macrophages Infected with Histoplasma capsulatum
| Autor: | Jan Rupp, Roger A. Fecher, George S. Deepe, Michael C. Horwath, Dirk Friedrich |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment Immunology Blotting Western Histoplasma Inflammation CREB Real-Time Polymerase Chain Reaction Article 03 medical and health sciences Mice 0302 clinical medicine Immune system medicine Immunology and Allergy Animals Histoplasmosis Mice Knockout Innate immune system Microscopy Confocal biology Macrophages biology.organism_classification Acquired immune system Flow Cytometry Hypoxia-Inducible Factor 1 alpha Subunit CREB-Binding Protein Interleukin-10 Mice Inbred C57BL Interleukin 10 Disease Models Animal 030104 developmental biology Cytokine biology.protein medicine.symptom 030215 immunology |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 197(2) |
| ISSN: | 1550-6606 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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