Discovering a sialic acid independent ligand for paired receptors Siglec‐5 and ‐14 (1003.5)

Siglec‐5 and Siglec‐14 are sialic acid (Sia)‐binding immunoreceptors found on myeloid lineage cells. Despite having identical ligand binding domains due to gene conversion, Siglec‐5 inhibits inflammatory responses after ligand engagement, but Siglec‐14 activates it instead. This unusual combination defines Siglec‐5 and ‐14 as paired receptors. Since sialoglycan ligands for Siglec‐5 are widely distributed on host cell surfaces, this is hypothesized to be a self‐recognition mechanism to prevent innate immune cells from attacking “self.” However, some bacterial pathogens take advantage of this self‐recognition system by engaging Siglec‐5, in order to suppress immune responses. Thus, it is hypothesized that Siglec‐14 emerged to counteract these “hijacking” pathogens. Although this model of Siglec‐14 evolution predicts uni‐directional gene conversion between Siglec‐5 and ‐14, the ligand binding domains of these receptors had undergone bi‐directional gene conversion instead. Also Siglec‐5 and ‐14 of some nonhuman primates have independently lost the ability to bind Sias due to a mutation in the Sia recognizing pocket. Thus, these receptors may have evolved to engage a Sia independent endogenous ligand. Preliminary evidence indicates that that such a ligand exists. Ongoing experiments are addressing whether this putative ligand‐receptor interaction modulates the pro‐inflammatory response. Grant Funding Source : Supported by NHLBI P01 HL057345