Siglec-14

Siglec-14 is an activating Siglec of the CD33-related family, formed coincident with Siglec-5 through a gene-conversion event: the first two exons (encoding the sialic acid-binding V-set domain) of SIGLEC14 and SIGLEC5 are virtually identical, so both proteins recognize the same α2,3-sialylated ligands, yet their signaling is opposite. Siglec-14 pairs with the adaptor DAP12 via a charged transmembrane arginine, transmitting activating signals through SYK that promote pro-inflammatory cytokine production and pathogen clearance in monocytes, macrophages and neutrophils. The Siglec-14/Siglec-5 paired activating/inhibitory receptor system balances inflammation: Siglec-14 engages sialylated microbes such as non-typeable Haemophilus influenzae and group B Streptococcus, driving bacteria-associated inflammatory responses, while Siglec-5 restrains them. A SIGLEC14 null polymorphism common in humans (frameshift deleting the activating receptor) leaves Siglec-5-mediated inhibition unopposed, correlating with exacerbated chronic obstructive pulmonary disease in smokers colonized by bacteria, and affecting tuberculosis and other infection outcomes, exemplifying how Siglec gene polymorphisms tune human inflammatory disease susceptibility.