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Published online March 10, 2008
doi:10.1083/jcb.200708043
The Journal of Cell Biology, Vol. 180, No. 5, 989-1003
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Tsai et al.
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Article

 Inhibition of "self" engulfment through deactivation of myosin-II at the phagocytic synapse between human cells

Richard K. Tsai1 and Dennis E. Discher1,2

1 Biophysical Engineering Laboratory, and 2 Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104

Correspondence to Dennis E. Discher: discher{at}seas.upenn.edu

Phagocytosis of foreign cells or particles by macrophages is a rapid process that is inefficient when faced with "self" cells that display CD47—although signaling mechanisms in self-recognition have remained largely unknown. With human macrophages, we show the phagocytic synapse at cell contacts involves a basal level of actin-driven phagocytosis that, in the absence of species-specific CD47 signaling, is made more efficient by phospho-activated myosin. We use "foreign" sheep red blood cells (RBCs) together with CD47-blocked, antibody-opsonized human RBCs in order to visualize synaptic accumulation of phosphotyrosine, paxillin, F-actin, and the major motor isoform, nonmuscle myosin-IIA. When CD47 is functional, the macrophage counter-receptor and phosphatase-activator SIRP{alpha} localizes to the synapse, suppressing accumulation of phosphotyrosine and myosin without affecting F-actin. On both RBCs and microbeads, human CD47 potently inhibits phagocytosis as does direct inhibition of myosin. CD47–SIRP{alpha} interaction initiates a dephosphorylation cascade directed in part at phosphotyrosine in myosin. A point mutation turns off this motor's contribution to phagocytosis, suggesting that self-recognition inhibits contractile engulfment.

Abbreviations used in this paper: DIC, differential interference contrast; NMM, nonmuscle myosin.


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