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Identification of human cathelicidin peptide LL-37 as a ligand for macrophage integrin αMβ2 (Mac-1, CD11b/CD18) that promotes phagocytosis by opsonizing bacteria

Authors Lishko V, Moreno B, Podolnikova N, Ugarova T

Received 1 March 2016

Accepted for publication 22 April 2016

Published 7 July 2016 Volume 2016:6 Pages 39—55


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Professor Nikolay Dokholyan

Valeryi K Lishko, Benjamin Moreno, Nataly P Podolnikova, Tatiana P Ugarova

Center for Metabolic and Vascular Biology, School of Life Sciences, Arizona State University, Tempe, AZ, USA

Abstract: LL-37, a cationic antimicrobial peptide, has numerous immune-modulating effects. However, the identity of a receptor that mediates the responses in immune cells remains uncertain. We have recently demonstrated that LL-37 interacts with the αMI-domain of integrin αMβ2 (Mac-1), a major receptor on the surface of myeloid cells, and induces a migratory response in Mac-1-expressing monocyte/macrophages as well as activation of Mac-1 on neutrophils. Here, we show that LL-37 and its C-terminal derivative supported strong adhesion of various Mac-1-expressing cells, including human embryonic kidney cells stably transfected with Mac-1, human U937 monocytic cells, and murine IC-21 macrophages. The cell adhesion to LL-37 was partially inhibited by specific Mac-1 antagonists, including monoclonal antibody against the αM integrin subunit and neutrophil inhibitory factor, and completely blocked when anti-Mac-1 antibodies were combined with heparin, suggesting that cell surface heparan sulfate proteoglycans act cooperatively with integrin Mac-1. Coating both gram-negative and gram-positive bacteria with LL-37 significantly potentiated their phagocytosis by macrophages, and this process was blocked by a combination of anti-Mac-1 monoclonal antibody and heparin. Furthermore, phagocytosis by wild-type murine peritoneal macrophages of LL-37-coated latex beads, a model of foreign surfaces, was several fold higher than that of untreated beads. In contrast, LL-37 failed to augment phagocytosis of beads by Mac-1-deficient macrophages. These results identify LL-37 as a novel ligand for integrin Mac-1 and demonstrate that the interaction between Mac-1 on macrophages and bacteria-bound LL-37 promotes phagocytosis.

Keywords: LL-37, integrin αMβ2, Mac-1, CD11b/CD18, phagocytosis, opsonin

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