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Ablation of CD22 Induces a Pro-Inflammatory Transcriptome Shift and Endocytic Deficits in M2-like Macrophages

ABSTRACT: The interactions between environmental glycans and glycan-binding proteins modulate a host of processes across biological systems. The Siglec/sialic acid axis has gained increasing attention as an immunologic checkpoint due to its involvement with reducing inflammatory processes and promoting tumor growth. Siglec-2, or CD22, has been extensively characterized as a co-receptor for the B cell receptor (BCR) and is critical for the prevention of self-reactive B cell responses through its recognition of α2,6-linked sialic acids. More recently, CD22 has emerged as an important receptor for macrophage biology. Here, we investigate the consequences of genetic ablation of CD22 in macrophages (CD22KO). Aged CD22KO mice developed a fatty liver phenotype similar to that seen in aged animals lacking hepatocyte α2,6-sialylation (HcKO). CD22KO bone marrow-derived macrophages (BMDMs) exhibited few differences in canonical markers of M1-like and M2-like polarization, but M2-like CD22KO BMDMs showed a pro-inflammatory shift in transcriptome and a reduction in endocytic and efferocytotic capacity. These data suggest that CD22 in M2-like macrophages is strongly associated with a homeostatic transcriptional profile, and directly participates in immunologically silent housekeeping functions such as clearance of sialylated-self debris through the Siglec-sialic acid axis.

ORGANISM(S): Mus musculus

PROVIDER: GSE310152 | GEO | 2025/12/04

REPOSITORIES: GEO

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Project description:Brain aging is a chronic process linked to inflammation, microglial activation, and oxidative damage, which can ultimately lead to neuronal loss. Sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC-11) is a human lineage-specific microglial cell surface receptor that recognizes α-2-8-linked oligo-/polysialylated glycomolecules with inhibitory effects on the microglial inflammatory pathways. Recently, the SIGLEC11 gene locus was prioritized as a top tier microglial gene with potential causality to Alzheimer’s disease, although its role in inflammation and neurodegeneration remains poorly understood. In this study, aged Siglec-11 transgenic (tg) mice, which expressed the human SIGLEC-11 receptor on microglia and tissue macrophages, were investigated. The brains of the Siglec-11 tg mice were analyzed in 6-month-old mature mice and 24-month-old aged mice using immunohistochemistry and transcriptomics. Results showed decreased density and fewer clusters of ionized calcium binding adaptor molecule 1 (Iba1)-positive microglial cells in the hippocampus and substantia nigra, as well as less lipid-laden microglia in the Siglec-11 tg in comparison to wildtype (WT) controls. Additionally, Siglec-11 tg mice exhibited less age-related neuronal loss in the substantia nigra pars compacta in comparison to WT mice. Transcriptome analysis revealed suppression of oxidative phosphorylation and inflammatory pathways in Siglec-11 tg brains at 6 months, with further suppression of complement and coagulation cascades at 24 months of age in comparison to WT mice. Gene transcript levels of the pro-inflammatory cytokines tumor necrosis factor alpha (Tnf) and interleukin 1 beta (Il-1b), as well as the oxidative stress markers cytochrome b-245 alpha and beta (Cyba and Cybb) and the nitric oxide synthase 2 (Nos2) were reduced in the brains of 24-month-old Siglec-11 tg mice relative to WT controls. Brains of 24-month-old Siglec-11 tg mice also exhibited lower gene transcription of complement component 4 and integrin alpha M (C4 and Itgam), along with the complement C1q subcomponents a and c (C1qa and C1qc). In summary, aged Siglec-11 tg mice displayed reduced brain inflammation and oxidative stress, as well as protection against age-related neuronal loss in the substantia nigra.

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Ablation of CD22 Induces a Pro-Inflammatory Transcriptome Shift and Endocytic Deficits in M2-like Macrophages

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