BOSTON - A molecular pathway known for responding to cellular stress also produces pain-inducing molecules in immune cells in mice, according to a new study by scientists at Dana-Farber Cancer Institute, Weill Cornell Medicine and Wake Forest University School of Medicine. The investigators found that blocking this pathway can reduce pain.
The findings, published online in the journal Science, emerged as the research team was studying the IRE1α-XBP1 pathway, which normally helps protect cells from the harmful accumulation of unfolded proteins in the endoplasmic reticulum, a cellular structure involved in the production of proteins and fats. The discovery that activation of IRE1α-XBP1 promotes pain may lead to new approaches to pain management that avoid the serious risks associated with widely used opioid pain medications.
"This is a promising discovery that has the potential to pave the way to new strategies for safer, more effective pain management, which is crucially important for improving public health," said co-corresponding author Laurie H. Glimcher, MD, president and CEO of Dana-Farber Cancer Institute. "It's another example of how understanding the role of the immune system more deeply offers the promise of better health outcomes for more people, ranging from pain management, to cancer and other diseases long-thought untreatable."
"We discovered that IRE1α-XBP1 activation controls a metabolic process in immune cells that enables the production of pain-inducing molecules called prostaglandins," said lead senior author Dr. Juan Cubillos-Ruiz, of Weill Cornell Medicine.
The researchers made the discovery when they triggered an inflammatory response in immune cells lacking components of the IRE1α-XBP1 pathway and analyzed how this altered the expression of other proteins in the cells. They found that two enzymes critically required for the production of prostaglandins, Cox-2 and mPGES-1, were reduced in immune cells that lacked IRE1α-XBP1.
The team also found that IRE1α-XBP1 activation in immune cells promotes the production of molecules called cytokines, which are involved in the perpetuation of pain. Their discovery may help explain why some people with inflammatory diseases or who have certain surgical procedures develop chronic pain.
To find out if blocking the IRE1α-XBP1 pathway could help alleviate pain, the team turned to co-corresponding author Dr. Edgar Alfonso Romero-Sandoval, an associate professor of anesthesiology at Wake Forest University School of Medicine in Winston-Salem, N.C. Dr. Romero-Sandoval and his team conducted experiments that demonstrated that mice engineered to selectively lack IRE1α-XBP1 in immune cells experience less pain in models that mimicked visceral or post-surgical pain.
They also found that two experimental small-molecule inhibitors, KIRA6 and MKC8866, that block the IRE1α-XBP1 pathway, also reduce pain responses in mice.
"We have identified a new mechanism in immune cells that promotes prostaglandin production," Dr. Romero-Sandoval said. "Disabling this pathway not only reduces pain, but also permits a faster recovery from it."
Dr. Romero-Sandoval said discovering new ways to treat pain is particularly crucial right now because of the ongoing opioid crisis. He noted that this very targeted approach could avoid some of the harmful side effects that have been seen with pain treatments that directly target nerve cells, such as opioids or anticonvulsants, or that obliterate the activity of immune cells, such as glucocorticoids.
Funding for the study was provided by: the Early-Career Investigator Award W81XWH-16-1-0438 of the Department of Defense; The Pershing Square Sohn Cancer Research Alliance; Weill Cornell Medicine Funds; Department of Anesthesiology-Wake Forest School of Medicine Funds; NIH grant R01CA112663; Plan Nacional de Salud y Farmacia Grant SAF2017-83079-R; and NIH grant 1S10OD017997-01A1.
Dr. Glimcher is the founder and chair of the scientific advisor board of Quentis, Inc., and serves on the board of directors at GlaxoSmithKline Pharmaceuticals and the Waters Corporation. She is also member of the scientific advisory board at AbproTherapeutics, RepareTherapeutics and KaleidoBioSciences, Inc. She holds equity in all these companies, as well as in Bristol-Myers Squibb, where she was a former director.
Dr. Cubillos-Ruiz receives stock options, royalties and is a paid scientific advisory board member for Quentis Therapeutics, Inc., a biotechnology company pursuing next-generation immuno-oncology research and drug development.
