title: AICAR Enhances the Phagocytic Ability of Macrophages towards Apoptotic Cells through P38 Mitogen Activated Protein Kinase Activation Independent of AMP-Activated Protein Kinase.
abstract: 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.
authors.affiliation: Departments of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea; Research Institute of Medical Sciences, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hui
authors.initials: H
authors.lastname: Quan
authors.affiliation: Departments of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Joung-Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Departments of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Departments of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Seong-Heon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Departments of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Jeong-Il
authors.initials: JI
authors.lastname: Choi
authors.affiliation: Departments of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea; Research Institute of Medical Sciences, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hong-Beom
authors.initials: HB
authors.lastname: Bae
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D007093:Imidazoles / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010587:Phagocytosis / Q000187:drug effects* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D007093:Imidazoles; D020930:MAP Kinase Kinase Kinases; D011725:Pyridines; D012265:Ribonucleotides; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C548179:Prkaa1 protein, mouse; C031143:AICA ribonucleotide; C093642:SB 203580