Study Reveals Signaling That Could Drive Chronic Inflammation and Perpetuate IBD, Cancer and Other Conditions

Turns out it’s a STING operation. Following tissue injury in the gut, stimulator of interferon genes (a.k.a. STING) activates the immune system to ramp up a repair response. The same signaling system also turns down the immune response once repair is complete.

Illustration showing gut bacteria inside the large intestine.

At least that’s how it’s supposed to work. In people with conditions driven by chronic inflammation – potentially including cancer, inflammatory bowel disease and obesity – STING signaling may be overactive, suggests a new study by Glen N. Barber, Ph.D., Eugenia J. Dodson Chair of Cancer Research at Sylvester Comprehensive Cancer Center and professor and chair of the Department of Cell Biology at the University of Miami Miller School of Medicine. The findings were published online in the December 26, 2017, Cell Reports.

The results hold promise for future drug development. “Our data would indicate that individuals with inflammatory bowel disease or other gut problems may be suffering from excessive STING signaling,” Barber said. “Thus, a drug that would specifically inhibit STING activity may help IBD-like diseases and other inflammatory diseases.”

The study reveals that STING is robustly activated in the case of DNA damage or tissue injury. Damaged regions can also be invaded by bacteria which in turn can strongly stimulate STING activity and pro-inflammatory cytokine production. These cytokines facilitate tissue repair and attract additional immune cells into the region to take care of any infection. STING also starts to make interleukin-10 (IL-10) to eventually control pro-inflammatory cytokine activity to avoid chronic inflammation.

STING recognizes chemicals produced by the bacteria called cyclic dinucleotides that trigger STING-dependent cytokine production. “But under normal conditions the interaction is slight, enabling just a little bit of pro- and anti-inflammatory cytokines to be made,” Barber said. “They balance one another out.”

In addition to demonstrating that unchecked STING signaling can cause inflammation, the current study builds on previous findings from Barber and team at the Miller School. “We discovered STING, STING signaling, the importance of STING in combating infectious disease and cancer,” Barber said.

Examples of earlier, related studies from Barber and colleagues include Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis (Cell Rep. 2016;14:282-97 and Diverse roles of STING-dependent signaling on the development of cancer (Oncogene. 2015;34:5302-8).

The study also contributes to a growing recognition of the essential role commensal bacteria in the gut – also known as the gut microbiome – play in regulating a person’s whole immune system.

“Bacteria in the gut prime the immune system to be ready to respond to infection,” Barber said. STING signaling in gut immune cells helps to maintain a healthy balance of bacteria.  When the gut bacterial balance is off, a condition known as dysbiosis, inflammation can go into overdrive.

So in addition to development of small therapeutic molecules that target STING signaling, direct modification of gut bacteria species could be feasible. “Scientists are already identifying harmful, pro-inflammatory bacteria which can outgrow the commensal or helpful bacteria in the gut,” Barber said. “They could be targeted for eradication using special antibiotics.”

Tags: colitis, Glen Barber, STING