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Pathogenic IgG sialylation drives macrophage immunometabolic dysfunction and lung immunopathology via a Siglec-1–FcγR–VDAC1 axis

ABSTRACT: Immunoglobulin G (IgG) Fc glycosylation critically regulates antibody effector functions, yet the pathogenic potential of early glycoform dynamics during acute viral infection remains poorly understood. Here, we identify a transient enrichment of sialylated IgG (Sia-IgG) during the early phase of SARS-CoV-2 infection that acts as a key driver of lung immunopathology. Contrary to the conventional anti-inflammatory role of sialylation, early-phase Sia-IgG fails to confer protection upon secondary viral challenge and instead aggravates lung injury despite reduced viral burden. Single-cell transcriptomic analysis of COVID-19 lungs reveals a selectively expanded SIGLEC1⁺ monocyte-derived macrophage population as a potential cellular target of this pathogenic signaling. Functional assays show that acute-phase IgG drives macrophage inflammatory infiltration in an FcγR-dependent manner. Moreover, acute-phase serum impairs phagocytic capacity and downregulates expression of the homeostatic marker CD206 in macrophages, indicative of a phenotypic shift toward a pro-inflammatory, dysfunctional state. Mechanistically, Sia-IgG coordinates the synergistic engagement of Siglec-1 and FcγRs, triggering mitochondrial immunometabolic collapse via VDAC1 oligomerization, excessive mitochondrial reactive oxygen species production, and impaired oxidative phosphorylation. Collectively, our findings define pathogenic IgG sialylation as a critical determinant of macrophage reprogramming, establishing a Siglec-1-FcγR-VDAC1 signaling axis that links humoral glycomic shifts to severe respiratory immunopathology during viral infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329962 | GEO | 2026/05/12

REPOSITORIES: GEO

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Project description:Maternal antibodies specific for antigens in the developing brain are implicated as risk factors for neurodevelopmental disorders, but how these antibodies interfere with neurodevelopment remain speculative. It has been postulated that immunoglobulin G-immune complexes (IgG-IC) activate Fc gamma receptors (FcγR) on non-immune cells in the brain, thereby modulating intracellular signaling and/or internalizing function-blocking antibodies specific for intracellular antigens. However, testing this hypothesis has been hindered by the paucity of data regarding FcγR in the developing brain. Thus, we first investigated FcγR expression in the brain of neonatal male and female rats using quantitative PCR analyses. FcgrIa, FcgrIIa, FcgrIIb, FcgrIIIa and Fcgrt transcripts were detectable in the cortex, hippocampus and cerebellum at postnatal days 1 and 7. These transcripts were also present in primary hippocampal and cortical cell cultures, where their expression was upregulated by IFNγ. In order to confirm protein abundance of FcγRIa, FcγRIIb and FcγRIIIa in cultured hippocampal and cortical neurons and astrocytes on the single cell and tissue level we used immunocytochemistry, western blotting, proteotype analysis, and flow cytometry. The data shows that a subpopulation of these cells co-express the excitatory FcγRIa and the inhibitory FcγRIIb. Functional analysis shows that exposure of hippocampal and cortical cell cultures to IgG-IC increased intracellular calcium and Erk phosphorylation, and triggered FcγR-mediated internalization of IgG. Collectively, these data demonstrate that developing neurons and astrocytes express signaling competent FcγR. which could establish a molecular mode of action of maternal antibodies could influence vulnerability to neurodevelopmental disorders via direct interactions with FcγR on non-immune cells in the developing brain. These findings support the hypothesis that maternal antibodies influence vulnerability to neurodevelopmental disorders via direct interactions with FcγR on non-immune cells in the developing brain.

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Pathogenic IgG sialylation drives macrophage immunometabolic dysfunction and lung immunopathology via a Siglec-1–FcγR–VDAC1 axis

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