NAIL: an evolutionarily conserved lncRNA essential for licensing coordinated activation of p38 and NFκB in colitis

Abstract

ObjectiveNFκB 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 networks.DesignUsing 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.ResultsNAIL 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.ConclusionNAIL 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.

Mast cells: Therapeutic targets for COVID‐19 and beyond

“…These proinflammatory and immunomodulatory mediators secreted by MCs contribute to host immunity and different diseases including but not limited to psoriasis, myalgic encephalomyelitis/chronic fatigue syndrome, interstitial cystitis, autism spectrum disorders, multiple sclerosis, rheumatoid arthritis, cancer, cardiovascular diseases, and other inflammation-related diseases besides allergy that can recognize pathogens. 33,58 These properties provide MCs with advantages to very rapidly act as sentinels to guard against a plethora of invading pathogens. This role of MCs in defense against invading pathogens was first reported in the context of parasitic infections.…”

“… 1 , 2 , 17 , 22 , 26 , 27 , 28 , 29 , 30 Hours later, numerous de novo synthesized cytokines and chemokines are also released from activated MCs as effectors of their functions. 1 , 2 , 17 , 22 , 23 , 25 , 31 , 32 , 33 , 34 Due to their distribution and expression of numerous arrays of membrane receptors, as well as the broad spectrum of inflammatory mediators they produce, 22 , 35 , 36 , 37 MCs can act as the first‐line responders in host defense against a number of pathogens and have long been recognized for their key effector role in allergic inflammation. However, recently there is evidence that MCs may be playing a key role in the pathogenesis of coronavirus/COVID‐19 disease.…”

“…Once activated, MCs can also newly synthesize lipid mediators such as prostaglandins and leukotrienes (1,2,17,22,(26)(27)(28)(29)(30). Hours later, numerous de novo synthesized cytokines and chemokines are also released from activated MCs as effectors of their functions (1,2,17,22,23,25,(31)(32)(33)(34). Due to their distribution and expression of numerous arrays of membrane receptors, as well as the broad spectrum of inflammatory mediators they produce (22,(35)(36)(37), MCs can act as the first-line responders in host defense against a number of pathogens against various inflammatory diseases (38-42) and have long been recognized for their key effector role in allergic inflammation.…”

The Role of lncRNAs in Regulating the Intestinal Mucosal Mechanical Barrier

“…However, little is known about the key regulators that activate, fine-tune, or turn off NFκB activity under inflammatory conditions. Akıncılar et al [103] designed the first genetic screening method to identify the specific lncRNA of NFκB and found a conservative lncRNA named NAIL. After a series of experiments, the authors found that NAIL can cooperate with another inflammatory factor, P38, to activate NF-κB and induce progenitor cells to differentiate into immature myeloid cells in the bone marrow, macrophages reassemble to the inflammatory region, and express inflammatory genes in colitis.…”

Hypoxia-induced PTTG3P contributes to colorectal cancer glycolysis and M2 phenotype of macrophage

“…PTENP1 can exert a growth-suppressive role by regulating cellular levels of PTEN [ 6 ]. NAIL identified in colitis patients that regulates inflammation through NFkB which is important for the inflammation [ 7 ], and cross-talk of NFkB and HIF signaling pathways in mediating the occurrence of inflammation. LncRNA PTTG3P (pituitary tumor-transforming 3, pseudogene, NR_002734), located at chromosome 8q13.1, was first reported in the study of the human pituitary tumor transforming gene ( hPTTG ) family in 2000 [ 8 ].…”