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Published October 11, 2017 | Supplemental Material + Erratum + Published
Journal Article Open

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


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.

Additional Information

© 2017 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received: 18 January 2017; Accepted: 10 August 2017; Published online: 11 October 2017. We thank I. Antoshechkin and V. Kumar at the Caltech Genetics and Genomics Laboratory for their assistance. We thank L.-F. Lu and A. Rudensky for providing miR-146a fl/fl mice. This work was supported by an NIH RO1AI079243 (D.B.), the Human Frontiers Science Foundation (M.M.) and National Research Service Award CA183220 (A.M.). Author Contributions: M.M., J.L.Z. and D.B. designed the study. M.M. conducted all the experimental work with assistance from A.M., J.L.Z., K.L. and Y.G.-F. G.K.M. and M.M. performed bioinformatics analysis. M.M. and D.B. wrote the manuscript with contributions from all authors. The authors declare no competing financial interests.


Li-Fan Lu and Alexander Y. Rudensky, who supplied miR-146a floxed mice used in this study, were inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article. The generation of the floxed mice has been described in detail by Cho and Lee et al.

Attached Files

Published - s41467-017-00972-z.pdf

Supplemental Material - 41467_2017_972_MOESM1_ESM.pdf

Supplemental Material - 41467_2017_972_MOESM2_ESM.pdf

Supplemental Material - 41467_2017_972_MOESM3_ESM.pdf

Supplemental Material - 41467_2017_972_MOESM4_ESM.xlsx

Erratum - s41467-018-05720-5.pdf


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