Journal Article

DKFZ-2023-01315

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Hypoxia-altered cholesterol homeostasis enhances the expression of interferon-stimulated genes upon SARS-CoV-2 infections in monocytes.

Bauer, R. ; Meyer, S. P. ; Raue, R. ; Palmer, M. A. ; Guerrero Ruiz, V. M. ; Cardamone, G. ; Rösser, S. ; Heffels, M. ; Roesmann, F. ; Wilhelm, A. ; Lütjohann, D. ; Zarnack, K. ; Fuhrmann, D. C.DKFZ* ; Widera, M. ; Schmid, T.DKFZ* ; Brüne, B.DKFZ*

2023
Frontiers Media Lausanne

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Please use a persistent id in citations: doi:10.3389/fimmu.2023.1121864

Abstract: Hypoxia contributes to numerous pathophysiological conditions including inflammation-associated diseases. We characterized the impact of hypoxia on the immunometabolic cross-talk between cholesterol and interferon (IFN) responses. Specifically, hypoxia reduced cholesterol biosynthesis flux and provoked a compensatory activation of sterol regulatory element-binding protein 2 (SREBP2) in monocytes. Concomitantly, a broad range of interferon-stimulated genes (ISGs) increased under hypoxia in the absence of an inflammatory stimulus. While changes in cholesterol biosynthesis intermediates and SREBP2 activity did not contribute to hypoxic ISG induction, intracellular cholesterol distribution appeared critical to enhance hypoxic expression of chemokine ISGs. Importantly, hypoxia further boosted chemokine ISG expression in monocytes upon infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Mechanistically, hypoxia sensitized toll-like receptor 4 (TLR4) signaling to activation by SARS-CoV-2 spike protein, which emerged as a major signaling hub to enhance chemokine ISG induction following SARS-CoV-2 infection of hypoxic monocytes. These data depict a hypoxia-regulated immunometabolic mechanism with implications for the development of systemic inflammatory responses in severe cases of coronavirus disease-2019 (COVID-19).

Keyword(s): COVID-19 ; SREBP2 ; cholesterol ; hypoxia ; immunometabolism ; systemic inflammation

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Frankfurt (FM01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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Database coverage:
; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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