Akıncılar SC, Wu L, NG QF, et al. Gut Epub ahead of print:24/11/2020. doi:10.1136/ gutjnl-2020-322980
Objective: NFκB is the key modulator in inflammatory disorders. However, the key regulators that activate,
fine-tune or shut off NFκB activity in inflammatory conditions are poorly understood. In this study, we aim
to investigate the roles that NFκB-specific long non-coding RNAs (lncRNAs) play in regulating inflammatory
Design: Using the first genetic-screen to identify NFκB-specific lncRNAs, we performed RNA-seq from the
p65-/- and Ikkβ-/- mouse embryonic fibroblasts and report the identification of an evolutionary conserved lncRNA designated mNAIL (mice) or hNAIL (human). hNAIL is upregulated in human inflammatory disorders, including UC. We generated mNAILΔNFκB mice, wherein deletion of two NFκB sites in the proximal promoter of mNAIL abolishes its induction, to study its function in colitis.
Results: NAIL regulates inflammation via sequestering and inactivating Wip1, a known negative regulator of
proinflammatory p38 kinase and NFκB subunit p65. Wip1 inactivation leads to coordinated activation of
p38 and covalent modifications of NFκB, essential for its genome-wide occupancy on specific targets. NAIL
enables an orchestrated response for p38 and NFκB coactivation that leads to differentiation of precursor
cells into immature myeloid cells in bone marrow, recruitment of macrophages to inflamed area and
expression of inflammatory genes in colitis.
Conclusion: NAIL directly regulates initiation and progression of colitis and its expression is highly correlated with NFκB activity which makes it a perfect candidate to serve as a biomarker and a therapeutic target for IBD and other inflammation-associated diseases.
VT lab is supported by NRF-CRP17-2017-02 grant and core funding from IMCB A*STAR. This research is supported by the Singapore Ministry of Health’s National Medical Research Council (NMRC/OFYIRG/18MAY-0008 to SCA). BU was supported by the SINGA scholarship awarded by A*STAR, Singapore. Ikawa lab.
is supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS) KAKENHI grants (JP18K14612 to TN and JP17H01394 to MI).