An NF-κB-microRNA regulatory network tunes macrophage inflammatory responses

• Published in: Nature communications Vol. 8; no. 1; pp. 851 - 13
• Main Authors: Mann, Mati, Mehta, Arnav, Zhao, Jimmy L., Lee, Kevin, Marinov, Georgi K., Garcia-Flores, Yvette, Lu, Li-Fan, Rudensky, Alexander Y., Baltimore, David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.10.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/2502/2055; 631/250/2504/342; 631/250/256/2516; 631/250/516/1909; Animals; Cell activation; HEK293 Cells; Humanities and Social Sciences; Humans; Immunity; Inflammation; Inflammatory response; Macrophages; Macrophages - immunology; Macrophages - metabolism; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs - metabolism; miRNA; multidisciplinary; Negative feedback; NF-kappa B - metabolism; NF-κB protein; Phenotype; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - metabolism; Regulators; Ribonucleic acid; RNA; Rodents; Science; Science (multidisciplinary); Signaling; Suppressor of Cytokine Signaling 1 Protein - metabolism; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00972-z

The innate inflammatory response must be tightly regulated to ensure effective immune protection. NF-κB is a key mediator of the inflammatory response, and its dysregulation has been associated with immune-related malignancies. Here, we describe a miRNA-based regulatory network that enables precise NF-κB activity in mouse macrophages. Elevated miR-155 expression potentiates NF-κB activity in miR-146a-deficient mice, leading to both an overactive acute inflammatory response and chronic inflammation. Enforced miR-155 expression overrides miR-146a-mediated repression of NF-κB activation, thus emphasizing the dominant function of miR-155 in promoting inflammation. Moreover, miR-155-deficient macrophages exhibit a suboptimal inflammatory response when exposed to low levels of inflammatory stimuli. Importantly, we demonstrate a temporal asymmetry between miR-155 and miR-146a expression during macrophage activation, which creates a combined positive and negative feedback network controlling NF-κB activity. This miRNA-based regulatory network enables a robust yet time-limited inflammatory response essential for functional immunity. MicroRNAs (miR) are important regulators of gene transcription, with miR-155 and miR-146a both implicated in macrophage activation. Here the authors show that NF-κB signalling, miR-155 and miR-146a form a complex network of cross-regulations to control gene transcription in macrophages for modulating inflammatory responses.