Hypoxia-controlled sterol and fatty acid synthesis with immune-modulatory consequences in myeloid cells

• Applicant: Professor Dr. Bernhard Brüne
• Subject Area: Cell Biology ; Biochemistry
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450517312

• Final Report Year: 2023

Final Report Abstract

Hypoxia occurs under physiological but also pathophysiological conditions, e.g. during cancer, atherosclerosis, or inflammation. We explored the impact of hypoxia towards lipid metabolism and questioned functional implications for monocytic cells. Hypoxia impaired oxygen-dependent cholesterol biosynthesis in THP-1 monocytic cells, causing accumulation of early but depletion of late cholesterol intermediates. Consequently, the transcription factor sterol regulatory element-binding protein (SREBP2), which causes the induction of nearly all cholesterol biosynthesis enzymes, was activated. Concomitantly, we identified a hypoxic immunometabolic crosstalk between altered cholesterol metabolism and the induction of a broad range of interferon (IFN)-stimulated genes (ISGs), known for their anti-viral function. Intracellular cholesterol distribution was linked to hypoxic induction of chemokine ISGs. Since IFN responses, but also impaired cholesterol metabolism, have a direct impact on viral infection, and severe respiratory infections are often accompanied by hypoxemia, we addressed effects of hypoxia on severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections. Most prominently, oxygen deprivation enhanced chemokine ISG expression in monocytes upon infection with SARS-CoV-2. Mechanistically, hypoxia sensitized toll-like receptor 4 (TLR4) signaling to its activation by the SARS-CoV-2 spike protein. Therefore, hypoxia might cause excessive production of chemokine ISGs by monocytes after exposure to SARS-CoV-2, which in turn may contribute to the development of a local inflammatory disease to a systemic inflammatory syndrome. We further observed an impaired activity of the oxygen-dependent desaturase SCD1 (stearoyl-CoA desaturase 1) and, accordingly, the ratio of monounsaturated to saturated fatty acids was reduced in chronic hypoxic macrophages. In addition, not only chronic hypoxia, but also the knockdown of SCD1 decreased the secretion of the C-C motif chemokine ligand 22 (CCL22) by macrophages and lowered the chemotactic activity of γδ T cells towards conditioned medium from macrophages. Since chronic hypoxia shapes the microenvironment of many tumors, the communication between tumor-associated macrophages and γδ T cells via the SCD1-CCL22 axis and its functional relevance in the tumor context should be examined in the future.

Publications

• Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment. Theranostics, 11(15), 7570-7588.
  Frank, Ann-Christin; Raue, Rebecca; Fuhrmann, Dominik C.; Sirait-Fischer, Evelyn; Reuse, Carsten; Weigert, Andreas; Lütjohann, Dieter; Hiller, Karsten; Syed, Shahzad Nawaz & Brüne, Bernhard
  
• Functional RNA Dynamics Are Progressively Governed by RNA Destabilization during the Adaptation to Chronic Hypoxia. International Journal of Molecular Sciences, 23(10), 5824.
  Bauer, Rebekka; Meyer, Sofie Patrizia; Kloss, Karolina Anna; Guerrero, Ruiz Vanesa Maria; Reuscher, Samira; Zhou, You; Fuhrmann, Dominik Christian; Zarnack, Kathi; Schmid, Tobias & Brüne, Bernhard
  
• miR-193a-3p increases glycolysis under hypoxia by facilitating Akt phosphorylation and PFKFB3 activation in human macrophages. Cellular and Molecular Life Sciences, 79(2).
  Fuhrmann, Dominik C. & Brüne, Bernhard
  
• Cholesterin-ISG-Wechselwirkung unter Hypoxie, „Gordon Research Conference: Immunometabolism in Health and Disease“ 2022 in Smithfield (RI, USA) and „2nd ImmunoSensation2-iFReC International School on Advanced Immunology“ 2023 in Maria Laach (Deutschland).
  Bauer R.
  
• Cholesterol metabolism in the regulation of inflammatory responses. Frontiers in Pharmacology, 14.
  Bauer, Rebekka; Brüne, Bernhard & Schmid, Tobias
  
• Hypoxia-altered cholesterol homeostasis enhances the expression of interferon-stimulated genes upon SARS-CoV-2 infections in monocytes. Frontiers in Immunology, 14.
  Bauer, Rebekka; Meyer, Sofie Patrizia; Raue, Rebecca; Palmer, Megan A.; Guerrero, Ruiz Vanesa Maria; Cardamone, Giulia; Rösser, Silvia; Heffels, Milou; Roesmann, Fabian; Wilhelm, Alexander; Lütjohann, Dieter; Zarnack, Kathi; Fuhrmann, Dominik Christian; Widera, Marek; Schmid, Tobias & Brüne, Bernhard
  
• Hypoxischee SCD1-CCL22-Regulation, „Resolution Days 3rd meeting“ 2023 in Besançon (Frankreich) and „10th International γδ T cell conference“ 2023 in Lissabon (Portugal).
  Guerrero Ruiz V.