CITED2 inhibits STAT1-IRF1 signaling and atherogenesis


Inflammation is a rapid response of the innate immune system to infection or sterile causes of trauma and tissue damage. Its main purpose is to alert, recruit, and activate cells of the immune system, mobilize the adaptive immune system, remove the infectious agent or other proinflammatory stimuli and, ultimately, repair the tissue damage. Macrophages play a pivotal role in orchestrating inflammation. They are principal components of the innate immune system and are highly plastic in the inflammatory response. Macrophages also play an important role in identifying host inflammatory signals with the help of numerous surface receptors. Identification of these inflammatory signals helps send an adequate signal to the cytoplasm and nucleus to initiate an appropriate immune response. Once these signals are activated, they result in increased expression/activation of transcriptional factors like HIF1-alpha, NFκB, STAT1, and IRFs. These transcriptional factors control the gene expression, which plays a vital role in the macrophage mediated inflammation. It appears that these transcriptional factors also play a role in hyperinflammatory responses resulting in excessive production of macrophagic cytokines, causing tissue damage, development of chronic ailments, and cell death. This dysregulated inflammatory response plays a role in autoimmune and inflammatory diseases like arthritis, atherosclerosis, irritable bowel syndrome, lupus, and sepsis. Fortunately, macrophages also contain certain intrinsic factors that help regulate this hyperinflammatory response. Identifying them may help reduce chronic inflammation and could be a therapeutic approach to treat chronic ailments.

An in depth study to elucidate the molecular mechanism underlying the role of transcriptional regulators in the hyperinflammatory responses of macrophages was recently reported by Atif Zafar, Hang Pong Ng, Rachel Diamond-Zaluski, Gun-Dong Kim, Ernest Ricky Chan, Jonathan Smith, and Professor Ganapati Mahabaleshwar from Case Western Reserve University School of Medicine in Cleveland. The research team identified intrinsic macrophagic factors playing a critical role in inflammation regulation and thus may have a role in treating chronic ailments, including reducing the risk of atherosclerotic plaque formation. The original research article is now published in the FASEB Journal. Professor Sally Dunwoodie from the Victor Chang Cardiac Research Institute in Australia was a co-author and a collaborator in the study.

The research team identified Cbp/ p300-interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (CITED2) as one of the vital intrinsic regulators of inflammatory genes that may help prevent inflammatory vascular wall disease. CITED2 is located in the nucleus. Early studies show that CITED2 plays an important role in cellular development and differentiation. Its mutation is associated with the development of congenital heart disease. These findings come from the genetically-modified mouse models. Not only that, but knocking out CITED2 also results in the maldevelopment of other body organs like adrenal glands, liver, neural tube defect, to mention few.

The researchers made several observations like CITED2 deficiency augmented TLR4-mediated IRFs target genes, thus resulting in greater expression of inflammatory mediators. Moreover, it boosted IRF1- regulated pro-inflammatory gene expression and increased IFNγ-induced STAT1 and IRF1 target gene expression. Therefore, macrophages deficient in CITED2 had an increased response to IFNγ-challenge. Ultimately, CITED2 deficiency exacerbated the formation of atherogenic plaques. It also promoted the formation of atherosclerotic lesions in atheroprone aortic sinus regions. Additionally, the researchers found knocking out IRF1 gene expression in macrophages could help reverse these hyperinflammatory and atherogenic responses. Thus, the study found that CITED2 helps control STAT1-IRF1 axis-mediated expression of inflammatory genes and thus may help prevent diet-induced atherogenesis.

Therefore, the study demonstrated that CITED2 is one of the most vital intrinsic factors in macrophages that help control hyperinflammatory responses by these immune cells. CITED2 helps regulate STAT1 and IRF1 mediated higher expression of inflammatory genes in macrophages and thus ultimately prevent the formation of atherosclerotic plaques. The researchers in the study confirmed CITED2 as a potent anti-inflammatory transcriptional regulator. In the future, modulating CITED2 activity could be a target of drugs for preventing diet-induced atherosclerosis.


Zafar A, Pong Ng H, Diamond-Zaluski R, et al. CITED2 inhibits STAT1-IRF1 signaling and atherogenesis. The FASEB Journal. 2021;35(9):e21833. doi:10.1096/fj.202100792R

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