Interaction between the integrin Mac-1 and signal regulatory protein α (SIRPα) mediates fusion in heterologous cells

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • Arizona State University
  • Czech Academy of Sciences
  • Vanderbilt University

Details

Original languageEnglish (US)
Pages (from-to)7833-7849
Number of pages17
JournalJournal of Biological Chemistry
Volume294
Issue number19
StatusPublished - May 10 2019
Peer-reviewedYes

Abstract

Macrophage fusion leading to the formation of multinucleated giant cells is a hallmark of chronic inflammation. Several membrane proteins have been implicated in mediating cell- cell attachment during fusion, but their binding partners remain unknown. Recently, we demonstrated that interleukin-4 (IL-4)- induced fusion of mouse macrophages depends on the integrin macrophage antigen 1 (Mac-1). Surprisingly, the genetic deficiency of intercellular adhesion molecule 1 (ICAM-1), an established ligand of Mac-1, did not impair macrophage fusion, suggesting the involvement of other counter-receptors. Here, using various approaches, including signal regulatory protein α (SIRPα) knockdown, recombinant proteins, adhesion and fusion assays, biolayer interferometry, and peptide libraries, we show that SIRPα, which, similar to ICAM-1, belongs to the Ig superfamily and has previously been implicated in cell fusion, interacts with Mac-1. The following results support the conclusion that SIRPα is a ligand of Mac-1: (a) recombinant ectodomain of SIRPα supports adhesion of Mac-1-expressing cells; (b) Mac-1-SIRPα interaction is mediated through the ligand-binding αMI-domain of Mac-1; (c) recognition of SIRPα by the αMIdomain conforms to general principles governing binding of Mac-1 to many of its ligands; (d) SIRPα reportedly binds CD47; however, anti-CD47 function-blocking mAb produced only a limited inhibition of macrophage adhesion to SIRPα; and (e) co-culturing of SIRPα- and Mac-1-expressing HEK293 cells resulted in the formation of multinucleated cells. Taken together, these results identify SIRPα as a counter-receptor for Mac-1 and suggest that the Mac-1-SIRPα interaction may be involved in macrophage fusion.

Citation formats

APA

Podolnikova, N. P., Hlavackova, M., Wu, Y., Yakubenko, V. P., Faust, J., Balabiyev, A., ... Ugarova, T. P. (2019). Interaction between the integrin Mac-1 and signal regulatory protein α (SIRPα) mediates fusion in heterologous cells. Journal of Biological Chemistry, 294(19), 7833-7849. https://doi.org/10.1074/jbc.RA118.006314

Harvard

Podolnikova, NP, Hlavackova, M, Wu, Y, Yakubenko, VP, Faust, J, Balabiyev, A, Wang, X & Ugarova, TP 2019, 'Interaction between the integrin Mac-1 and signal regulatory protein α (SIRPα) mediates fusion in heterologous cells', Journal of Biological Chemistry, vol. 294, no. 19, pp. 7833-7849. https://doi.org/10.1074/jbc.RA118.006314