Inverse Correlation between IL-10 and HIF-1? in Macrophages Infected with Histoplasma capsulatum.

ABSTRACT: Hypoxia-inducible factor (HIF)-1? 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-1? 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-1?-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-1? 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 (M?s) constituted most IL-10-producing cells. Deletion of HIF-1? in neutrophils or dendritic cells did not alter fungal burden, thus implicating M?s as the pivotal cell in host resistance. HIF-1? was stabilized in M?s following infection. Increased activity of the transcription factor CREB in HIF-1?-deficient M?s drove IL-10 production in response to H. capsulatum IL-10 inhibited M? control of fungal growth in response to the activating cytokine IFN-?. Thus, we identified a critical function for M? HIF-1? in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1? and CREB is critical for activation of M?s by IFN-? and effective handling of H. capsulatum.

SUBMITTER: Fecher RA 

PROVIDER: S-EPMC4935642 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature