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

Mati MannDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA. [email protected]Arnav MehtaDavid Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USAJimmy L. ZhaoDepartment of Medicine, New York Presbyterian Hospital, Weill Cornell Medical College, 525 E 68th Street, New York, NY, 10065, USAKevin LeeDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USAGeorgi K. MarinovDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USAYvette Garcia-FloresDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USALi‐Fan LuCenter for Microbiome Innovation, University of California, La Jolla, San Diego, CA, 92093, USAAlexander Y. RudenskyHoward Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USADavid BaltimoreDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA. [email protected]

2017en

ABI

Annotatsiya

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.

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DOI: 10.1038/s41467-017-00972-z

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