| First Author | Fecher RA | Year | 2016 |
| Journal | J Immunol | Volume | 197 |
| Issue | 2 | Pages | 565-79 |
| PubMed ID | 27271565 | Mgi Jnum | J:297699 |
| Mgi Id | MGI:6479167 | Doi | 10.4049/jimmunol.1600342 |
| Citation | Fecher RA, et al. (2016) Inverse Correlation between IL-10 and HIF-1alpha in Macrophages Infected with Histoplasma capsulatum. J Immunol 197(2):565-79 |
| abstractText | Hypoxia-inducible factor (HIF)-1alpha 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-1alpha 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-1alpha-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-1alpha 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 (Mvarphis) constituted most IL-10-producing cells. Deletion of HIF-1alpha in neutrophils or dendritic cells did not alter fungal burden, thus implicating Mvarphis as the pivotal cell in host resistance. HIF-1alpha was stabilized in Mvarphis following infection. Increased activity of the transcription factor CREB in HIF-1alpha-deficient Mvarphis drove IL-10 production in response to H. capsulatum IL-10 inhibited Mvarphi control of fungal growth in response to the activating cytokine IFN-gamma. Thus, we identified a critical function for Mvarphi HIF-1alpha in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1alpha and CREB is critical for activation of Mvarphis by IFN-gamma and effective handling of H. capsulatum. |
