At the front line of our immune system macrophages are standing by, detecting pathogens and kicking off an inflammatory response when needed. Understanding how these immune cells know when to go all-out and when to keep calm is critical to finding new ways to strike the right chord in cases where the immune system overreacts, such as in sepsis and other autoimmune disorders.

Researchers at the University of California (UC) San Diego School of Medicine report they have discovered a protein that acts as a brake on macrophages. Their findings, “TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin,” were published in the Proceedings of the National Academy of Sciences.

“Sensing of pathogens by Toll-like receptor 4 (TLR4) induces an inflammatory response; controlled responses confer immunity but uncontrolled responses cause harm. Here we define how a multimodular scaffold, GIV, or Girdin, titrates such inflammatory response in macrophages,” noted the researchers.

When the team deleted the GIV gene from mouse macrophages, the immune cells overreacted to small amounts of live bacteria. Mice with colitis and sepsis fared worse when lacking the GIV gene in their macrophages. They also created peptides that mimic GIV, which allowed them to put the brakes on mouse macrophages on command. When treated with the GIV-mimic peptide, the mice’s inflammatory response was tempered.

“When a patient dies of sepsis, he or she does not die due to the invading bacteria themselves, but from an overreaction of their immune system to the bacteria,” explained Pradipta Ghosh, MD, professor at UC San Diego School of Medicine and Moores Cancer Center. “It’s similar to what we’re seeing now with dangerous ‘cytokine storms’ that can result from infection with the novel coronavirus SARS-CoV-2. Macrophages, and the cytokines they produce, are the body’s own immune-stimulating agents and when produced in excessive amounts, they do more harm than good.”

Further observation revealed that the GIV protein works together with TLR4. Outside of the cell, TLR4 is like an antenna, searching for signs of invading pathogens. Inside the cell, GIV waits between the receptor’s two “feet.” When in place, GIV keeps the feet apart, and nothing happens. When GIV is removed, the TLR4 feet touch and sends off immune-stimulating signals.

“We were surprised at just how fluid the immune system is when it encounters a pathogen,” said Ghosh, who is also director of the Institute for Network Medicine and executive director of the HUMANOID Center of Research Excellence at UC San Diego School of Medicine. “Macrophages don’t need to waste time and energy producing more or less GIV protein, they can rapidly dial their response up or down simply by moving it around, and it appears that such regulation happens at the level of gene transcription.”

The researchers are looking forward to investigating the factors that determine how the GIV brake remains in place when macrophages are resting or is removed to mount a response to a credible threat. The Institute for Network Medicine at UC San Diego School of Medicine recently received a $5 million grant from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Ghosh shares this award with her colleagues Debashis Sahoo, PhD, assistant professor at UC San Diego School of Medicine and Jacobs School of Engineering, and Soumita Das, PhD, associate professor of pathology at UC San Diego School of Medicine.

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