Recognition of S100 proteins by Signal Inhibitory Receptor on Leukocytes‐1 negatively regulates human neutrophils

Signal inhibitory receptor on leukocytes‐1 (SIRL‐1) is an inhibitory receptor with a hitherto unknown ligand, and is expressed on human monocytes and neutrophils. SIRL‐1 inhibits myeloid effector functions such as reactive oxygen species (ROS) production. In this study, we identify S100 proteins as SIRL‐1 ligands. S100 proteins are composed of two calcium‐binding domains. Various S100 proteins are damage‐associated molecular patterns (DAMPs) released from damaged cells, after which they initiate inflammation by ligating activating receptors on immune cells. We now show that the inhibitory SIRL‐1 recognizes individual calcium‐binding domains of all tested S100 proteins. Blocking SIRL‐1 on human neutrophils enhanced S100 protein S100A6‐induced ROS production, showing that S100A6 suppresses neutrophil ROS production via SIRL‐1. Taken together, SIRL‐1 is an inhibitory receptor recognizing the S100 protein family of DAMPs. This may help limit tissue damage induced by activated neutrophils.