Inflammation is a fundamental aspect of the immune system that helps control the spread of pathogens through a variety of cell signaling methods. Yet, in its attempt to “do good,” there are several scenarios where the inflammatory response can grow out of control and cause detrimental effects. Now, investigators at UT Southwestern (UTSW) have released new data identifying two proteins that act as gatekeepers to dampen a potentially life-threatening immune response to chronic infection.

The proteins in questions—the transcription factors SIX1 and SIX2—activate cellular pathways required for fetal development and later switch to a new role in which they repress these pathways in adult immune system cells. The findings from the new study were published recently in Nature through an article titled “A NIK–SIX signaling axis controls inflammation by targeted silencing of non-canonical NF-κB.”

“This work provides insight into the molecular components required to limit tissue damage associated with uncontrolled inflammation, such as in septic shock, and reveals how cancer cells may suppress the innate immune system during tumor genesis,” explained senior study investigator Neal Alto, PhD, professor of microbiology at UTSW.

Transcription factors are proteins that bind to special regions of DNA to turn genes on (activate them) or off (repress them). Alto continued, stating that “one of the surprising findings was that a transcription activator that is essential for the development of tissues and organs has been repurposed as a transcriptional repressor in the immune system. While transcription factors can be used differently in various stages of life, a switch from a transcriptional activator in the fetus to a suppressor in adult immune cells is infrequent.”

This new study provides a framework for studying a new pathway for controlling inflammation, which could be important for developing new drugs. It also might explain how cancer cells develop chemotherapy resistance.

Moreover, the researchers found that the two proteins showed inhibitory activities when bound to genes involved in inflammation. Specifically, SIX1 and SIX2 appeared to dampen the body’s immune response to prevent damage associated with a potentially life-threatening condition called a cytokine storm, which can occur in chronic inflammatory conditions.

“A cytokine storm can occur when the body’s immune cells and activators (cytokines) show an overresponse to a health threat such as the flu,” Alto explained.

An experiment with transgenic mice found that expression of SIX1 in adulthood conferred near-complete recovery following exposure to a toxin released by gram-negative bacteria that can set off a cytokine storm. The two SIX proteins seem to dampen the response of the so-called noncanonical NF-κB pathway, a signaling cascade that is instrumental in the development of the lymph organs, the maturation of the immune system’s antibody-producing B cells, and the development of bone cells. The same pathway is involved in the body’s immune defense in adulthood.

These studies, which initially focused on bacteria and viruses, also shed light on mechanisms of cancer cell resistance to drug treatment. In one series of experiments, the team found that cancer cells derived from patients with treatment-resistant non-small cell lung cancer expressed high levels of the SIX1 and SIX2 proteins. The scientists used the CRISPR-Cas9 gene-editing technology to remove the genes that produce those two proteins, making the cancer cells dramatically more sensitive to a promising drug class called SMAC mimetics.

“In summary, we have established that SIX family transcription factors function as immunological gatekeepers, regulating the activity of inflammatory genes in response to noncanonical NF-κB pathway activation,” Alto concluded. “These findings indicate that disruption of this pathway could have important consequences for the pathogenesis of human disease, including cancer.”

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