Recent studies have suggested that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (
AICAR) increases macrophage phagocytosis through
adenosine monophosphate-activated
protein kinase (AMPK). However, little information is available on the effects of
AICAR on the clearance of apoptotic cells by macrophages, known as efferocytosis, which is essential in maintaining tissue homeostasis and resolving
inflammation.
AICAR increased
p38 MAPK activation and the phagocytosis of apoptotic cells by macrophages, which were inhibited by the
p38 MAPK inhibitor,
SB203580, the
TGF-beta-activated kinase 1 (TAK1) inhibitor, (5Z)-7-oxozeaenol, and
siRNA-mediated knock-down of p38α.
AICAR increased phosphorylation of Akt, but the inhibition of PI3K/Akt activity using
LY294002 did not affect the
AICAR-induced changes in efferocytosis in macrophages. CGS15943, a non-selective
adenosine receptor antagonist, did not affect
AICAR-induced changes in efferocytosis, but
dipyridamole, an
adenosine transporter inhibitor, diminished the
AICAR-mediated increases in efferocytosis.
AICAR-induced
p38 MAPK phosphorylation was not inhibited by the
AMPK inhibitor, compound C, or
siRNA-mediated knock-down of AMPKα1. Inhibition of AMPK using compound C or 5'-iodotubercidin did not completely block
AICAR-mediated increases in efferocytosis. Furthermore,
AICAR also increased the removal of apoptotic neutrophils or thymocytes in mouse lungs. These results reveal a novel mechanism by which
AICAR increases macrophage-mediated phagocytosis of apoptotic cells and suggest that
AICAR may be used to treat efferocytosis-related inflammatory conditions.