Negative elongation factor complex enables macrophage inflammatory responses by controlling anti-inflammatory gene expression

• Published in: The Journal of immunology (1950) 2020-05, Vol.204 (1_Supplement), p.152-152.28
• Main Authors: Yu, Li, Zhang, Bin, Deochand, Dinesh, Sacta, Maria A., Coppo, Maddalena, Shang, Yingli, Guo, Ziyi, Rollins, David A., Tharmalingam, Bowranigan, Li, Rong, Chinenov, Yurii, Rogatsky, Inez, Hu, Xiaoyu
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.204.Supp.152.28

Studies on macrophage gene expression have historically focused on events leading to RNA polymerase II recruitment and transcription initiation whereas the contribution of post-initiation steps to macrophage activation remains poorly understood. Here, we report widespread promoter-proximal RNA polymerase II pausing in resting macrophages, marked by broad co-localization of the negative elongation factor (NELF) complex and facilitated by PU.1. Upon inflammatory stimulation, over 60% of activated transcriptome is regulated by polymerase pause-release and a transient genome-wide NELF dissociation from chromatin, unexpectedly, independent of CDK9, a presumed NELF kinase. Genetic disruption of NELF in macrophages enhanced transcription of AP-1-encoding Fos and Jun and, consequently, AP-1 targets including Il10. Augmented expression of IL-10, a critical anti-inflammatory cytokine, in turn, attenuated production of pro-inflammatory mediators and, ultimately, macrophage-mediated inflammation in vivo. Together, these findings establish a previously unappreciated role of NELF in constraining transcription of inflammation inhibitors thereby enabling inflammatory macrophage activation.