Adenylate Kinase 4 Promotes Inflammatory Gene Expression via Hif1α and AMPK in Macrophages
Journal
Frontiers in immunology
Journal Volume
12
Date Issued
2021
Author(s)
Abstract
Macrophages comprise the front line of defense against various pathogens. Classically activated macrophages (M1), induced by IFN-γ and LPS, highly express inflammatory cytokines and contribute to inflammatory processes. By contrast, alternatively activated macrophages (M2) are induced by IL-4 and IL-13, produce IL-10, and display anti-inflammatory activity. Adenylate kinase 4 (Ak4), an enzyme that transfers phosphate group among ATP/GTP, AMP, and ADP, is a key modulator of ATP and maintains the homeostasis of cellular nucleotides which is essential for cell functions. However, its role in regulating the function of macrophages is not fully understood. Here we report that Ak4 expression is induced in M1 but not M2 macrophages. Suppressing the expression of Ak4 in M1 macrophages with shRNA or siRNA enhances ATP production and decreases ROS production, bactericidal ability and glycolysis in M1 cells. Moreover, Ak4 regulates the expression of inflammation genes, including Il1b, Il6, Tnfa, Nos2, Nox2, and Hif1a, in M1 macrophages. We further demonstrate that Ak4 inhibits the activation of AMPK and forms a positive feedback loop with Hif1α to promote the expression of inflammation-related genes in M1 cells. Furthermore, RNA-seq analysis demonstrates that Ak4 also regulates other biological processes in addition to the expression of inflammation-related genes in M1 cells. Interestingly, Ak4 does not regulate M1/M2 polarization. Taken together, our study uncovers a potential mechanism linking energy consumption and inflammation in macrophages.
Subjects
AK4; AMPK; HIF1α; classically activated macrophages (M1); inflammation
Other Subjects
adenosine triphosphate; adenylate kinase; citrinin; gamma interferon; glutathione; guanosine triphosphate; hypoxia inducible factor 1alpha; interleukin 13; interleukin 1beta; interleukin 6; polyvinylidene fluoride; short hairpin RNA; small interfering RNA; tumor necrosis factor; adenosine triphosphate; adenylate kinase; Hif1a protein, mouse; hydroxymethylglutaryl coenzyme A reductase kinase; hypoxia inducible factor 1alpha; reactive oxygen metabolite; AMPK signaling; animal experiment; animal model; antiinflammatory activity; Article; bacterium transduction; cell function; controlled study; energy consumption; enzyme activity; enzyme linked immunosorbent assay; female; flow cytometry; gene expression; gene silencing; genetic transfection; glycolysis; high throughput sequencing; homeostasis; hypoxia; inflammation; M1 macrophage; M2 macrophage; macrophage; macrophage function; microarray analysis; mouse; nonhuman; oxidative phosphorylation; oxygen consumption; phagocytosis; polarization; protein expression; real time polymerase chain reaction; RNA isolation; RNA sequencing; upregulation; Western blotting; animal; C57BL mouse; cell culture; cell polarity; inflammation; macrophage; metabolism; physiology; Adenosine Triphosphate; Adenylate Kinase; AMP-Activated Protein Kinases; Animals; Cell Polarity; Cells, Cultured; Female; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Reactive Oxygen Species
Type
journal article