CITED2 restrains proinflammatory macrophage activation and response

Gun Dong Kim, Riku Das, Xiaoquan Rao, Jixin Zhong, Jeffrey A. Deiuliis, Diana L. Ramirez-Bergeron, Sanjay Rajagopalan, Ganapati H. Mahabeleshwar

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Macrophages are strategically distributed in mammalian tissues and play an essential role in priming the immune response. However, macrophages need to constantly strike a balance between activation and inhibition states to avoid a futile inflammatory reaction. Here, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage proinflammatory activation. Gain- and loss-of-function studies revealed that CITED2 is required for optimal peroxisome proliferator-activated receptor gamma (PPARγ) activation and attendant select anti-inflammatory gene expression in macrophages. More importantly, deficiency of CITED2 resulted in significant attenuation of rosiglitazone-induced PPARγ activity, PPARγ recruitment to target gene promoters, and anti-inflammatory target gene expression in macrophages. Interestingly, deficiency of Cited2 strikingly heightened proinflammatory gene expression through stabilization of hypoxia-inducible factor 1 alpha (HIF1α) protein in macrophages. Further, overexpression of Egln3 or inhibition of HIF1α in Cited2-deficient macrophages completely reversed elevated proinflammatory cytokine/chemokine gene expression. Importantly, mice bearing a myeloid cell-specific deletion of Cited2 were highly susceptible to endotoxin-induced sepsis symptomatology and mortality. Collectively, our observations identify CITED2 as a novel negative regulator of macrophage proinflammatory activation that protects the host from inflammatory insults.

Original languageEnglish (US)
Article numbere00452-17
JournalMolecular and Cellular Biology
Volume38
Issue number5
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

Fingerprint

Macrophage Activation
Macrophages
PPAR gamma
Gene Expression
Hypoxia-Inducible Factor 1
rosiglitazone
Anti-Inflammatory Agents
Trans-Activators
Myeloid Cells
Chemokines
Aspartic Acid
Endotoxins
Glutamic Acid
Sepsis
Cytokines
Mortality
Genes
Proteins

Keywords

  • Cited2
  • HIF1α
  • Inflammation
  • Innate immunity
  • Macrophage
  • PPARγ

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Kim, G. D., Das, R., Rao, X., Zhong, J., Deiuliis, J. A., Ramirez-Bergeron, D. L., ... Mahabeleshwar, G. H. (2018). CITED2 restrains proinflammatory macrophage activation and response. Molecular and Cellular Biology, 38(5), [e00452-17]. https://doi.org/10.1128/MCB.00452-17

CITED2 restrains proinflammatory macrophage activation and response. / Kim, Gun Dong; Das, Riku; Rao, Xiaoquan; Zhong, Jixin; Deiuliis, Jeffrey A.; Ramirez-Bergeron, Diana L.; Rajagopalan, Sanjay; Mahabeleshwar, Ganapati H.

In: Molecular and Cellular Biology, Vol. 38, No. 5, e00452-17, 01.03.2018.

Research output: Contribution to journalArticle

Kim, GD, Das, R, Rao, X, Zhong, J, Deiuliis, JA, Ramirez-Bergeron, DL, Rajagopalan, S & Mahabeleshwar, GH 2018, 'CITED2 restrains proinflammatory macrophage activation and response', Molecular and Cellular Biology, vol. 38, no. 5, e00452-17. https://doi.org/10.1128/MCB.00452-17
Kim GD, Das R, Rao X, Zhong J, Deiuliis JA, Ramirez-Bergeron DL et al. CITED2 restrains proinflammatory macrophage activation and response. Molecular and Cellular Biology. 2018 Mar 1;38(5). e00452-17. https://doi.org/10.1128/MCB.00452-17
Kim, Gun Dong ; Das, Riku ; Rao, Xiaoquan ; Zhong, Jixin ; Deiuliis, Jeffrey A. ; Ramirez-Bergeron, Diana L. ; Rajagopalan, Sanjay ; Mahabeleshwar, Ganapati H. / CITED2 restrains proinflammatory macrophage activation and response. In: Molecular and Cellular Biology. 2018 ; Vol. 38, No. 5.
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