SOCS3 is a modulator of human macrophage phagocytosis

Peter Gordon, Blessing Okai, Joseph I Hoare, Lars P Erwig, Heather M Wilson

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19 Citations (Scopus)
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Abstract

Suppressor of cytokine signaling (SOCS) proteins are
recognized as key feedback inhibitors modulating the
inflammatory activities of macrophages, but comparatively
little is known about whether and how they affect
phagocytosis. Here, we evaluated the role of SOCS3 in
driving the inflammatory phenotype and phagocytic
uptake of apoptotic cells by human macrophages and
the signaling pathways that are necessary for efficient
phagocytosis. In M1-activated human monocyte-derived
macrophages, SOCS3 silencing, using short interfering
RNA technology, resulted in a decreased expression of
proinflammatory markers and an increased expression
of M2 macrophage markers. Strikingly, we demonstrated
for the first time that SOCS3 knockdown
significantly enhances the phagocytic capacity of M1
macrophages for carboxylate-modified beads and
apoptotic neutrophils. With the use of live-cell video
microscopy, we showed that SOCS3 knockdown radically
affects the temporal dynamics of particle engulfment,
enabling more rapid uptake of a second
target and delaying postengulfment processing, as
evidenced by deferred acquisition of phagosome
maturation markers. SOCS3 knockdown impacts on
phagocytosis through increased PI3K and Ras-related
C3 botulinum toxin substrate 1 (Rac1) activity, pathways
essential for engulfment and clearance of apoptotic
cells. Enhanced phagocytosis in SOCS3-
silenced cells was reversed by pharmacological PI3K
inhibition. Furthermore, we revealed that actin polymerization,
downstream of PI3K/Rac1 activation, was
significantly altered in SOCS3-silenced cells, providing
a mechanism for their greater phagocytic activity. The
findings support a new model, whereby SOCS3 not
only plays an important role in driving macrophage
inflammatory responses but modulates key signaling pathways organizing the actin cytoskeleton to regulate
the efficiency of phagocytic processes. J. Leukoc. Biol.
100: 000–000; 2016.
Original languageEnglish
Pages (from-to)771-780
Number of pages10
JournalJournal of Leukocyte Biology
Volume100
Issue number4
Early online date22 Apr 2016
DOIs
Publication statusPublished - Oct 2016

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Keywords

  • live-cell imaging
  • PI3K
  • Rac1

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