Restraint of Fumarate Accrual by HIF-1α Preserves miR-27a-Mediated Limitation of Interleukin 10 during Infection of Macrophages by Histoplasma capsulatum

Hypoxia-inducible factor 1α (HIF-1α) regulates the immunometabolic phenotype of macrophages, including the orchestration of inflammatory and antimicrobial processes. Macrophages deficient in HIF-1α produce excessive quantities of the anti-inflammatory cytokine interleukin 10 (IL-10) during infection...

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Published in:	mBio Vol. 12; no. 6; p. e0271021
Main Authors:	Evans, Heather M, Schultz, Destiny F, Boiman, Adam J, McKell, Melanie C, Qualls, Joseph E, Deepe, Jr, George S
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 21-12-2021
Subjects:	Animals Citric Acid Cycle Fumarates - metabolism Histoplasma Histoplasma - genetics Histoplasma - physiology Histoplasmosis - genetics Histoplasmosis - metabolism Histoplasmosis - microbiology Host-Microbial Interactions Humans hypoxia inducible factor 1 Hypoxia-Inducible Factor 1, alpha Subunit - genetics Hypoxia-Inducible Factor 1, alpha Subunit - metabolism innate immunity Interleukin-10 - genetics Interleukin-10 - metabolism lung Macrophages - metabolism Macrophages - microbiology Mice MicroRNAs - genetics MicroRNAs - metabolism mitochondrial metabolism Research Article lung innate immunity Histoplasma hypoxia inducible factor 1 mitochondrial metabolism
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Summary:	Hypoxia-inducible factor 1α (HIF-1α) regulates the immunometabolic phenotype of macrophages, including the orchestration of inflammatory and antimicrobial processes. Macrophages deficient in HIF-1α produce excessive quantities of the anti-inflammatory cytokine interleukin 10 (IL-10) during infection with the intracellular fungal pathogen Histoplasma capsulatum (R. A. Fecher, M. C. Horwath, D. Friedrich, J. Rupp, G. S. Deepe, J Immunol 197:565-579, 2016, https://doi.org/10.4049/jimmunol.1600342). Thus, the macrophage fails to become activated in response to proinflammatory cytokines and remains the intracellular niche of the pathogen. Here, we identify the tricarboxylic acid (TCA) cycle metabolite fumarate as the driver of IL-10 during macrophage infection with H. capsulatum in the absence of HIF-1α. Accumulation of fumarate reduced expression of a HIF-1α-dependent microRNA (miRNA), miR-27a, known to mediate decay of mRNA. Inhibition of fumarate accrual limited IL-10 and fungal growth. Our data demonstrate the critical role of HIF-1α in shaping appropriate TCA cycle activity in response to infection and highlight the consequences of a dysregulated immunometabolic response. Histoplasma capsulatum and related species are intracellular fungal pathogens endemic to broad regions of the globe, including the Americas, Africa, and Asia. While most infections resolve with mild or no symptoms, failure of the host to control fungal growth produces severe disease. Previously, we reported that loss of a key transcriptional regulator, hypoxia-inducible factor 1α (HIF-1α), in macrophages led to a lethal failure to control growth of (R. A. Fecher, M. C. Horwath, D. Friedrich, J. Rupp, G. S. Deepe, J Immunol 197:565-579, 2016, https://doi.org/10.4049/jimmunol.1600342). Inhibition of phagocyte activation due to excessive interleukin 10 by HIF-1α-deficient macrophages drove this outcome. In this study, we demonstrate that HIF-1α maintains contextually appropriate TCA cycle metabolism within -infected macrophages. The absence of HIF-1α results in excessive fumarate production that alters miRNA-27a regulation of interleukin-10. HIF-1α thus preserves the capacity of macrophages to transition from a permissive intracellular niche to the site of pathogen killing.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Destiny F. Schultz, Mayo Clinic Graduate School of Biomedical Science, Mayo Clinic, Rochester, Minnesota, USA.
ISSN:	2150-7511 2150-7511
DOI:	10.1128/mBio.02710-21