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

5 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Kim, G. D., Das, R., Rao, X., Zhong, J., Deiuliis, J. A., Ramirez-Bergeron, D. L., Rajagopalan, S., & 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