Leukocyte integrin Mac-1 (CD11b/CD18, αMβ2, CR3) acts as a functional receptor for platelet factor 4

Valeryi K. Lishko, Valentin P. Yakubenko, Tatiana P. Ugarova, Nataly P. Podolnikova
2018 Journal of Biological Chemistry  
Edited by Peter Cresswell Platelet factor 4 (PF4) is one of the most abundant cationic proteins secreted from ␣-granules of activated platelets. Based on its structure, PF4 was assigned to the CXC family of chemokines and has been shown to have numerous effects on myeloid leukocytes. However, the receptor for PF4 remains unknown. Here, we demonstrate that PF4 induces leukocyte responses through the integrin Mac-1 (␣ M ␤ 2 , CD11b/CD18). Human neutrophils, monocytes, U937 monocytic and HEK293
more » ... cytic and HEK293 cells expressing Mac-1 strongly adhered to immobilized PF4 in a concentration-dependent manner. The cell adhesion was partially blocked by anti-Mac-1 mAb and inhibition was enhanced when anti-Mac-1 antibodies were combined with glycosaminoglycans, suggesting that cell-surface proteoglycans act cooperatively with Mac-1. PF4 also induced Mac-1-dependent migration of human neutrophils and murine WT, but not Mac-1-deficient macrophages. Coating of Escherichia coli bacteria or latex beads with PF4 enhanced their phagocytosis by macrophages by ϳ4-fold, and this process was blocked by different Mac-1 antagonists. Furthermore, PF4 potentiated phagocytosis by WT, but not Mac-1-deficient macrophages. As determined by biolayer interferometry, PF4 directly bound the ␣ M I-domain, the major ligand-binding region of Mac-1, and this interaction was governed by a K d of 1.3 ؎ 0.2 M. Using the PF4-derived peptide library, synthetic peptides duplicating the ␣ M I-domain recognition sequences and recombinant mutant PF4 fragments, the binding sites for ␣ M I-domain were identified in the PF4 segments Cys 12 -Ser 26 and Ala 57 -Ser 70 . These results identify PF4 as a ligand for the integrin Mac-1 and suggest that many immune-modulating effects previously ascribed to PF4 are mediated through its interaction with Mac-1.
doi:10.1074/jbc.ra117.000515 pmid:29540475 fatcat:dhyavwatgvgyrbvcm4uddp4jxy