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

Mati Mann (), Arnav Mehta, Jimmy L. Zhao, Kevin Lee, Georgi K. Marinov, Yvette Garcia-Flores, Li-Fan Lu, Alexander Y. Rudensky and David Baltimore ()
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Mati Mann: Division of Biology and Biological Engineering, California Institute of Technology
Arnav Mehta: Division of Biology and Biological Engineering, California Institute of Technology
Jimmy L. Zhao: New York Presbyterian Hospital, Weill Cornell Medical College
Kevin Lee: Division of Biology and Biological Engineering, California Institute of Technology
Georgi K. Marinov: Division of Biology and Biological Engineering, California Institute of Technology
Yvette Garcia-Flores: Division of Biology and Biological Engineering, California Institute of Technology
Li-Fan Lu: University of California
Alexander Y. Rudensky: Ludwig Center at Memorial Sloan-Kettering Cancer Center
David Baltimore: Division of Biology and Biological Engineering, California Institute of Technology

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00972-z

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