Signal Inhibitory Receptor on Leukocytes-1 recognizes S100 proteins

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. We here 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. We conclude that SIRL-1 is an inhibitory receptor recognizing the S100 protein family of DAMPs. ### Competing Interest Statement The authors have declared no competing interest. * ### Abbreviations SIRL-1 : Signal inhibitory receptor on leukocytes-1 LAIR-1 : Leukocyte-associated immunoglobulin-like receptor-1 ROS : reactive oxygen species; DAMP : damage-associated molecular pattern; MS : mass spectrometry; FBS : fetal bovine serum; Fmoc : 9-fluoronylmethoxycarbonyl