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Siglecs are sialic acid specific I‑type lectins that are characterized by an extracellular domain (ECD) with an N‑terminal Ig‑like V‑set domain followed by varying numbers of Ig‑like C2‑set domains. Mouse Siglec‑E, also known as Myeloid Inhibitory Siglec (MIS), is an 80 ‑ 85 kDa member of the CD33‑related subfamily of Siglecs. Rodent and primate Siglec gene families have significantly diverged, and Siglec‑9 is the most likely human ortholog of mouse Siglec‑E. Siglec‑E is expressed as a heavily N‑glycosylated disulfide‑linked homodimer and shows binding preference for disialic acids in the alpha 2‑8 linkage. Siglec‑E is up‑regulated and additionally phosphorylated following cellular stimulation by a variety of TLR agonists. Siglec‑E signaling negatively regulates the LPS‑induced production of TNF‑ alpha and IL‑6 by macrophages. Its up‑regulation in macrophages parallels the development of endotoxin tolerance. Siglec‑E recognition of sialylated determinants on virulent T. cruzi contributes to the suppression of dendritic cell IL‑12 p40 production.