The Kinase Akt1 Controls Macrophage Response to Lipopolysaccharide by Regulating MicroRNAs

• Published in: Immunity (Cambridge, Mass.) Vol. 31; no. 2; pp. 220 - 231
• Main Authors: Androulidaki, Ariadne, Iliopoulos, Dimitrios, Arranz, Alicia, Doxaki, Christina, Schworer, Steffen, Zacharioudaki, Vassiliki, Margioris, Andrew N., Tsichlis, Philip N., Tsatsanis, Christos
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.08.2009; Elsevier Limited
• Subjects: Animals; Cell Line; CELLIMMUNO; Experiments; Gene expression; Immune Tolerance - immunology; Kinases; Lipopolysaccharides - immunology; Macrophages - enzymology; Macrophages - immunology; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; MicroRNAs - biosynthesis; MicroRNAs - genetics; MOLIMMUNO; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rodents; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins - immunology; Suppressor of Cytokine Signaling Proteins - metabolism; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism; MOLIMMUNO; CELLIMMUNO
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2009.06.024

MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here, we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e and miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4), whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signaling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1−/− macrophages exhibited increased responsiveness to LPS in culture and Akt1−/− mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1−/− macrophages restored sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression.