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Anti\u2010spike IgG of critically ill COVID\u201019 patients induces excessive inflammation by activation of Fc gamma receptors (Fc\u03b3Rs) 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\u201019\u2010specific hyperinflammation. In this study, we identified that anti\u2010spike 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\u2010spike IgG\u2010induced hyperinflammation. Remarkably, while excessive proinflammatory cytokine production by macrophages is critically dependent on simultaneous stimulation with viral stimuli and anti\u2010spike IgG complexes, we show that the required metabolic reprogramming is specifically driven by anti\u2010spike IgG complexes. These findings provide new insights into the metabolic pathways driving hyperinflammation by macrophages in the context of severe COVID\u201019. Targeting of these pathways may reveal new possibilities to counteract pathological inflammatory responses in severe COVID\u201019 and related diseases.<\/jats:p>","DOI":"10.1002\/eji.70087","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T14:38:20Z","timestamp":1766155100000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hyperinflammation by Human Macrophages Induced by SARS\u2010CoV\u20102 Anti\u2010Spike IgG Is Dependent on Glucose and Fatty Acid Metabolism"],"prefix":"10.1002","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9113-3292","authenticated-orcid":false,"given":"Chiara E.","family":"Geyer","sequence":"first","affiliation":[{"name":"Center for Infection and Molecular Medicine, Amsterdam institute for Immunology and Infectious diseases, Amsterdam University Medical Center (UMC) University of Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8656-3135","authenticated-orcid":false,"given":"Lu\u00eds","family":"Almeida","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8807-7795","authenticated-orcid":false,"given":"Lynn","family":"Mes","sequence":"additional","affiliation":[{"name":"Center for Infection and Molecular Medicine, Amsterdam institute for Immunology and Infectious diseases, Amsterdam University Medical Center (UMC) University of Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Otto","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. 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