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Inverse correlation between IL-10 and HIF-1a in macrophages infected with Histoplasma capsulatum

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2016, PhD, University of Cincinnati, Medicine: Immunology.
Hypoxia inducible factor (HIF)-1a 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-1a 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-1a-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-1a in neutrophils or alveolar macrophages and dendritic cells did not alter fungal burden thus implicating macrophages as the pivotal cell in host resistance. HIF-1a was stabilized in macrophages following infection. The absence of myeloid HIF-1a 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. IL-10 blockade restored protective immunity to the mutant mice. Macrophages constituted the majority of IL-10 producing cells. Increased activity of the transcription factor CREB in HIF-1a-deficient macrophages drove IL-10 production in response to H. capsulatum. IL-10 inhibited macrophage control of fungal growth in response to the activating cytokine IFN-?. Thus, we identified a critical function for macrophage HIF-1a in tempering IL-10 production following infection. We established that transcriptional regulation of IL-10 by HIF-1a and CREB is critical for activation of macrophages by IFN-? and effective handling of H. capsulatum. Our data provide insight into the mechanism of HIF-1a 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-1a and IL-10 regulation in innate immune defense against H. capsulatum.
George Deepe, M.D. (Committee Chair)
James Bridges, Ph.D. (Committee Member)
Charles Caldwell, Ph.D. (Committee Member)
Gurjit Hershey, M.D. Ph.D. (Committee Member)
David Hildeman, Ph.D. (Committee Member)
Joseph Qualls, Ph.D. (Committee Member)
188 p.

Recommended Citations

Citations

  • Fecher, R. A. (2016). Inverse correlation between IL-10 and HIF-1a in macrophages infected with Histoplasma capsulatum [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1468512555

    APA Style (7th edition)

  • Fecher, Roger. Inverse correlation between IL-10 and HIF-1a in macrophages infected with Histoplasma capsulatum. 2016. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1468512555.

    MLA Style (8th edition)

  • Fecher, Roger. "Inverse correlation between IL-10 and HIF-1a in macrophages infected with Histoplasma capsulatum." Doctoral dissertation, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1468512555

    Chicago Manual of Style (17th edition)