CITED2 restrains pro-inflammatory macrophage activation and response.

Macrophages are strategically distributed in mammalian tissues and play an essential role in priming immune response. However, macrophages need to constantly strike a balance between activation and inhibition state to avoid a futile inflammatory reaction. Herein, we identify the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2) as a potent repressor of macrophage pro-inflammatory 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 in rosiglitazone-induced PPARγ activity, PPARγ recruitment to target gene promoters and anti-inflammatory target gene expression in macrophages. Interestingly, deficiency of Cited2 strikingly heightened pro-inflammatory 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 pro-inflammatory cytokine/chemokine gene expression. Importantly, mice bearing a myeloid-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 pro-inflammatory activation and protect the host from inflammatory insults.