Signal inhibitory receptor on leukocytes‐1 recognizes bacterial and endogenous amphipathic α‐helical peptides

Signal inhibitory receptor on leukocytes‐1 (SIRL‐1) is a negative regulator of myeloid cell function and dampens antimicrobial responses. We here show that different species of the genus Staphylococcus secrete SIRL‐1‐engaging factors. By screening a library of single‐gene transposon mutants in Staphylococcus aureus, we identified these factors as phenol‐soluble modulins (PSMs). PSMs are amphipathic α‐helical peptides involved in multiple aspects of staphylococcal virulence and physiology. They are cytotoxic and activate the chemotactic formyl peptide receptor 2 (FPR2) on immune cells. Human cathelicidin LL‐37 is also an amphipathic α‐helical peptide with antimicrobial and chemotactic activities, structurally and functionally similar to α‐type PSMs. We demonstrate that α‐type PSMs from multiple staphylococcal species as well as human cathelicidin LL‐37 activate SIRL‐1, suggesting that SIRL‐1 recognizes α‐helical peptides with an amphipathic arrangement of hydrophobicity, although we were not able to show direct binding to SIRL‐1. Upon rational peptide design, we identified artificial peptides in which the capacity to ligate SIRL‐1 is segregated from cytotoxic and FPR2‐activating properties, allowing specific engagement of SIRL‐1. In conclusion, we propose staphylococcal PSMs and human LL‐37 as a potential new class of natural ligands for SIRL‐1.