2. Academic Validation
  3. Hyperinflammation by Human Macrophages Induced by SARS-CoV-2 Anti-Spike IgG Is Dependent on Glucose and Fatty Acid Metabolism

Hyperinflammation by Human Macrophages Induced by SARS-CoV-2 Anti-Spike IgG Is Dependent on Glucose and Fatty Acid Metabolism

  • Eur J Immunol. 2025 Dec;55(12):e70087. doi: 10.1002/eji.70087.
Chiara E Geyer 1,  Luís Almeida 2,  Lynn Mes 1,  Frank Otto 2,  W Ashwin Mak 1,  Graham A Heieis 2,  Jennifer Veth 1,  Steven W de Taeye 3,  Tom G Caniels 3,  Tom P L Bijl 3,  Marit J van Gils 3,  Menno de Winther 4,  Amsterdam UMC COVID‐19 Biobank,  Jan Van den Bossche 5,  Hung-Jen Chen 1,  Riekelt H Houtkooper 6 7 8,  Bart Everts 2,  Jeroen den Dunnen 2
Affiliations

Affiliations

  • 1 Center for Infection and Molecular Medicine, Amsterdam institute for Immunology and Infectious diseases, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands.
  • 2 Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
  • 3 Department of Medical Microbiology, Amsterdam institute for Immunology and Infectious diseases, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands.
  • 4 Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • 5 Department of Molecular Cell Biology and Immunology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • 6 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • 7 Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands.
  • 8 Amsterdam Cardiovascular Sciences Institute, Amsterdam, The Netherlands.
PMID: 41416928 DOI: 10.1002/eji.70087
Abstract

Severe COVID-19 is an immunological disorder characterized by excessive immune activation following Infection with SARS-CoV-2, which typically occurs around the time of seroconversion. Anti-spike IgG of critically ill COVID-19 patients induces excessive inflammation by activation of Fc gamma receptors (FcγRs) on human alveolar macrophages, leading to tissue damage, pulmonary edema, and coagulopathy. While metabolic reprogramming of immune cells is critical for the induction of inflammatory responses, still little is known about the metabolic pathways that are involved in COVID-19-specific hyperinflammation. In this study, we identified that anti-spike IgG immune complexes (ICs) induce rapid metabolic reprogramming of alveolar macrophages, which is essential for the induction of inflammation. Through functional inhibition, we identified that glycolysis, fatty acid synthesis, and pentose phosphate pathway (PPP) activation are critical for anti-spike IgG-induced hyperinflammation. Remarkably, while excessive proinflammatory cytokine production by macrophages is critically dependent on simultaneous stimulation with viral stimuli and anti-spike IgG complexes, we show that the required metabolic reprogramming is specifically driven by anti-spike IgG complexes. These findings provide new insights into the metabolic pathways driving hyperinflammation by macrophages in the context of severe COVID-19. Targeting of these pathways may reveal new possibilities to counteract pathological inflammatory responses in severe COVID-19 and related diseases.

Keywords

COVID‐19; antibodies; immunometabolism; macrophage.

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