Identification of the Antimicrobial Peptide LL‐37 as a Ligand for Integrin αMβ2 (Mac‐1, CD11b/CD18) Reveals its Role in Macrophage Phagocytosis

Abstract

The cathelicidin peptide LL‐37 has numerous immune‐modulating effects and has been implicated in a bactericidal effect. However, the mechanisms by which LL‐37 mediates these activities remain unclear. Our recent elucidation of the recognition specificity of integrin Mac‐1, a major receptor on the surface of myeloid cells, indicated that LL‐37 contains several putative Mac‐1 recognition motifs and could potentially interact with the receptor. Using a peptide library spanning the sequence of LL‐37, we show that the αMI‐domain of Mac‐1 bound several overlapping LL‐37‐derived peptides. The full‐length peptide and its C‐terminal derivative (18‐37) supported strong adhesion of various Mac‐1‐expressing cells, including human U937 monocytic cells, murine IC‐21 macrophages and HEK293 cells transfected with Mac‐1. The cell adhesion to LL‐37 was partially inhibited by mAbs against the αM and β2 integrin subunits, and completely blocked when anti‐Mac‐1 antibodies were combined with heparin, suggesting that cell surface proteoglycans act cooperatively with integrin Mac‐1. Coating both Gram‐negative and Gram‐positive bacteria with LL‐37 significantly enhanced their phagocytosis by macrophages, and this process was blocked by a combination of anti‐Mac‐1 mAbs and heparin. Phagocytosis by murine peritoneal macrophages of LL‐37‐coated latex beads, a model of foreign surfaces, was several fold higher than that of untreated beads. Furthermore, LL‐37 potentiated phagocytosis by wild‐type, but not Mac‐1‐deficient macrophages. These results identify LL‐37 as a ligand for integrin Mac‐1 and opsonin, revealing a new aspect of LL‐37 action.NIH Support: NIH HL 63199