CITED2 Restrains Proinflammatory Macrophage Activation and Response

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 <i>Cited2</i> strikingly heightened proinflammatory gene expression through stabilization of hypoxia-inducible factor 1 alpha (HIF1α) protein in macrophages. Further, overexpression of <i>Egln3</i> or inhibition of HIF1α in <i>Cited2</i>-deficient macrophages completely reversed elevated proinflammatory cytokine/chemokine gene expression. Importantly, mice bearing a myeloid cell-specific deletion of <i>Cited2</i> 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.