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Abstract
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 since both mouse and human granulomas induced by this pathogenic fungus develop hypoxic microenvironments during the early adaptive immune response. Here we demonstrated that myeloid HIF-1α- deficient mice exhibited elevated fungal burden during the innate immune response (prior to seven days post-infection) as well as decreased survival in response to a sublethal inoculum of H. capsulatum. Deletion of HIF-1α in neutrophils or alveolar macrophages and DCs did not alter fungal burden thus implicating M&phis;s as the pivotal cell in host resistance. HIF-1α was stabilized in M&phis;s following infection. 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 antiinflammatory cytokine IL-10. IL-10 blockade restored protective immunity to the mutant mice. Macrophages (M&phis;) constituted the majority of IL-10 producing cells. Increased activity of the transcription factor CREB in HIF-1α-deficient M&phis;s drove IL-10 production in response to H. capsulatum. IL-10 inhibited M&phis; control of fungal growth in response to the activating cytokine IFN-γ. Thus, we identified a critical function for M&phis; 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 M&phis; by IFN-γ and effective handling of H. capsulatum.
Our data provide insight into the mechanism of HIF-1α elevation in the host response to H. capsulatum. In addition, we provide gene expression data that may help elucidate the immune mechanisms that lead to fungal growth restriction. In summary, this investigation provides novel insights into HIF-1á and IL-10 regulation in innate immune defense against H. capsulatum.