| Siglec‑1 (CD169, sialoadhesin, SIGLEC1) is a macrophage-restricted, type I transmembrane receptor of the sialic acid–binding Ig‑like lectin (Siglec) family that recognizes α2,3‑linked sialylated glycoconjugates and functions as a key adhesion and uptake receptor at interfaces between myeloid cells, lymphocytes, and pathogens. The extracellular region contains a single N‑terminal V‑set Ig domain that harbors the conserved sialic acid–binding site followed by a long series of C2‑set Ig domains, making Siglec‑1 the largest Siglec and enabling extended reach into the vascular or lymphoid lumen, while the short cytoplasmic tail lacks canonical inhibitory ITIM motifs but can support endocytosis and signaling crosstalk through associated adaptors. Expression is largely confined to subsets of tissue-resident and marginal-zone macrophages and interferon-inducible myeloid cells, where Siglec‑1 is upregulated by type I interferons and inflammatory cues and localizes to plasma membrane domains that engage sialylated ligands on erythrocytes, B cells, CD8 T cells, NK cells, granulocytes, and activated lymphocytes, promoting cell–cell adhesion, clustering, and immune synapse formation. Ligand binding drives sialic acid–dependent capture and internalization of sialylated particles and pathogens, including enveloped viruses and bacteria, and Siglec‑1-positive macrophages and dendritic cells use this receptor to mediate uptake, phagocytosis, and routing of antigens toward antigen-presenting compartments, which supports MHC class II and cross-presentation to T cells and equips these cells to link innate recognition with adaptive priming. In the context of viral infection, Siglec‑1 recognizes sialylated gangliosides such as GM3 on the membranes of HIV‑1 and other enveloped viruses, concentrating virions in nondegradative compartments and delivering them across infectious synapses to CD4 T cells in a process termed trans‑infection, thereby enhancing viral dissemination while the myeloid cell may remain nonproductively infected. The same receptor–glycolipid mechanism operates for several other enveloped viruses, including SARS‑CoV‑2, where Siglec‑1-expressing macrophages capture virions, modulate cytokine responses, and can either contribute to hyperinflammation or, in some settings, limit viral spread and support effective T cell responses, highlighting the dual host-protective and pathogen-exploited roles of this lectin. Siglec‑1-positive macrophages also participate in tissue immunoregulation; they populate marginal zones of spleen and lymph node and inflamed tissues, clear sialylated debris and apoptotic material, and influence lymphocyte proliferation and tolerance versus immunity, and their presence in autoimmune lesions such as rheumatoid arthritis and multiple sclerosis aligns with a role in shaping chronic inflammation. Expression of CD169 on blood monocytes or tissue macrophages serves as a sensitive interferon-response biomarker in systemic lupus erythematosus and viral infections, and CD169 immunohistochemistry is widely used to identify activated myeloid subsets and map neuroinflammatory foci, for example in active multiple sclerosis plaques or other CNS inflammatory conditions. These features define Siglec‑1/CD169 as a structurally distinctive, sialic-acid–dependent adhesion and endocytic receptor that integrates type I interferon signaling, pathogen capture, antigen presentation, and myeloid–lymphoid cross‑talk. |
