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

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 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. 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 (Mϕ) constituted the majority of IL-10 producing cells. Deletion of HIF-1α in neutrophils or DCs did not alter fungal burden thus implicating Mϕs as the pivotal cell in host resistance. HIF-1α was stabilized in Mϕ 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 Mϕ by IFN-γ and effective handling of H. capsulatum.

HIF1α is an essential regulator of steroidogenesis in the adrenal gland

“…Ablation of HIF1α revealed an important role for this transcription factor in steroidogenesis, which concurs with results from previous studies (20,50). However, our findings that HIF1α deletion results in the upregulation of mRNA of a vast majority of steroid-related enzymes is counterintuitive to the nature of this transcription factor (12, 51), and therefore we believe this effect is most likely indirect with potential involvement of one or more transcriptional repressors (13,52,53). This type of transcriptional regulation of adrenal steroidogenesis has already been suggested with miRNAs, which are endogenous noncoding single-stranded small RNAs that suppress the expression of various target genes (54 Glucocorticoids and aldosterone are both essential for homeostasis and their substantial increase in P2H1 mice was intriguing, given their pivotal role in immune suppression (3,58) and blood pressure regulation, respectively.…”

Myeloid Cell–Derived HIF-1α Promotes Control of Leishmania major

“…In addition to the indirect antimicrobial actions of HIF-1a that are exerted via its targets NOS2 [this study and (58)] and cathelicidin (12), HIF-1a expression in myeloid cells might have immunoregulatory functions in infectious diseases. For instance, in mouse models of Histoplasma capsulatum infection, HIF-1a suppressed the production of IL-10 and, thereby, helped to fight the infection (68). Moreover, infection of mice with Helicobacter pylori resulted in HIF-1a accumulation in myeloid cells, which was not required for H. pylori elimination by phagocytes but was required for termination of tissue inflammation.…”

Inhibition of hypoxia‐associated response and kynurenine production in response to hyperbaric oxygen as mechanisms involved in protection against experimental cerebral malaria

“…Our results indicate that endothelial cells are an important target of HBO-induced protective molecular mechanisms during ECM, probably by downregulation of the proinflammatory hypoxic response (10,29). Thus, to address whether during ECM, HBO inhibits the hypoxia-triggered response in brain endothelial cells through inhibition of HIF-1a-dependent transcriptional activity, we created a Tie2cre HIF-1a fl/fl mouse strain that lacked HIF-1a in endothelial cells (19). As Ahr mRNA and Hmox1 expression is regulated by HIF-1a-induced transcriptional activity, we tested whether HIF-1a deletion in brain endothelial cells would affect expression of both genes during infection with PbA.…”

“…Female C57BL/6 mice (7-10 wk old) were purchased from the Multidisciplinary Center for Biological Investigation on Laboratory Animal Science, University of Campinas, and maintained in our specific pathogen-free animal facility. Hypoxia-inducible factor 1-a flox/flox (HIF-1a fl/fl ) mice were provided by Dr. George Deepe (University of Cincinnati, Cincinnati, OH, USA) (19) and crossed with Tie2cre to generate endothelial cell conditional knockout mice for HIF-1a (Tie2cre HIF-1a fl/fl ).…”