Two MicroRNAs and NF-kB Act in a Unique Regulatory Network to Ensure Precision of the Acute Inflammatory Response in Macrophages

The innate inflammatory response must be tightly regulated to ensure effective immune protection while avoiding inflammation-related pathologies. The transcription factor NF-kB is a critical mediator of the inflammatory response, and its dysregulation has been associated with immune related malignancies. We herein show that miR-155, miR-146a and NF-kB form a regulatory network that tunes the macrophage inflammatory response in mice. We show that elevated miR-155 expression potentiates NF-kB activity in miR-146a deficient mice, thus leading to an overactive acute inflammatory response and chronic inflammation. Enforced miR-155 expression overrides miR-146a-mediated repression of NF-kB activation, thus emphasizing that miR-155 plays a dominant, downstream role in promoting inflammation. We further show that 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 forms a combined positive and negative feedback network on NF-kB activity. This miRNA based regulatory network enables a robust and time-limited inflammatory response essential for functional immunity. RNA-seq of wild-type and microRNA-146/155 knock-out bone marrow derived macrophages after LPS stimulation