CITED2 limits pathogenic inflammatory gene programs in myeloid cells

Pong Ng, Hang and Kim, Gun‐Dong and Ricky Chan, E. and Dunwoodie, Sally L. and Mahabeleshwar, Ganapati H. (2020) CITED2 limits pathogenic inflammatory gene programs in myeloid cells. The FASEB Journal. ISSN 0892-6638

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Monocyte-derived macrophages are the major innate immune cells that provide the first line of cellular defense against infections or injuries. These recruited macrophages at the site of inflammation are exposed to a broad range of cytokines that categorically incite a robust pro-inflammatory response. However, macrophage pro-inflammatory activation must be under exquisite control to avert unbridled inflammation. Thus, endogenous mechanisms must exist that rigorously preserve macrophage quiescence and yet, allow nimble pro-inflammatory macrophage response with precise spatiotemporal control. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a critical intrinsic negative regulator of inflammation, which broadly attenuates pro-inflammatory gene programs in macrophages. Our in vivo studies revealed that myeloid-CITED2 deficiency significantly heightened macrophages and neutrophils recruitment to the site of inflammation. Our integrated transcriptomics and gene set enrichment analysis (GSEA) studies uncovered that CITED2 deficiency broadly enhances NFκB targets, IFNγ/IFNα responses, and inflammatory response gene expression in macrophages. Using complementary gain- and loss-of-function studies, we observed that CITED2 overexpression attenuate and CITED2 deficiency elevate LPS-induced NFκB transcriptional activity and NFκB-p65 recruitment to target gene promoter in macrophages. More importantly, blockade of NFκB signaling completely reversed elevated pro-inflammatory gene expression in macrophages. Collectively, our findings show that CITED2 restrains NFκB activation and curtails broad pro-inflammatory gene programs in myeloid cells.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine, Health and Life Sciences > School of Medicine
Depositing User: Repository Administrator
Date Deposited: 27 Jul 2020 22:19
Last Modified: 19 Oct 2021 00:54

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