Akt1 controls macrophage response to LPS by regulating microRNAs

By Ariadne Androulidaki, D. Iliopoulos, A. Arranz, Christina Doxaki, Steffen Schworer, V. Zacharioudaki, A. Margioris, P. Tsichlis, C. Tsatsanis. Immunity, 2009

602 citations recorded by the source corpus.

SUMMARY MicroRNAs regulated by LPS target genes that contribute to the inflammatory phenotype. Here we show that Akt1, which is activated by LPS, differentially regulates miRNAs including let-7e, miR-155, miR-181c and miR125b. In silico analyses and transfection studies revealed that let-7e represses TLR4 while miR-155 represses SOCS1, two genes critical for LPS-driven TLR signalling, 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 restores 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f0e926a9b00b8106afe53c115ace7b456819fc67

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Citations in the corpus

MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development (2010, background): “Among these, SHIP1 and SOCS1 have been shown to be directly targeted by miR-155 (Androulidaki et al., 2009; Lu et al., 2009; O'Connell et al., 2009), and to function by negatively regulating cytokine production by DCs (An et al.”
Physiological and pathological roles for microRNAs in the immune system (2010, background): “Interestingly, AKT signalling has recently been shown to repress miR-155 expression in macrophage”
MicroRNAs: the fine-tuners of Toll-like receptor signalling (2011, background): “In mouse peritoneal macrophages, the induction of let-7e expression decreases cell surface expression of TLR4, the mRNA of which contains a let-7 target sit”
microRNA regulation of inflammatory responses. (2012, background): “LPS-induced upregulation of SHIP is essential for endotoxin tolerance.”
Diversity, Mechanisms and Significance of Macrophage Plasticity (2019, background): “expression of miR-155, thus establishing a negative feedback loop mechanism that self-limit the proinflammatory response of macrophage and have a significant impact in controlling ET, as reported in miR-155 knock-in mice, showing high levels of TNF and susceptibility to LPS shock (93).”
Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses (2010, positive): “…(cancer-associated micro-RNA), is constitutively expressed in high amounts in Treg cells in a Foxp3-dependent manner, whereas T cells lacking Foxp3, B cells, and myeloid cells transiently upregulate miR-155 upon activation (Androulidaki et al., 2009; O’Connell et al., 2007; Thai et al., 2007).”
Alternative activation of macrophages: mechanism and functions. (2010, background): “The kinase Akt regulates LPS-induced microRNA in macrophages and is implicated in LPS tolerance (Androulidaki et al., 2009).”