Immune cells have lasting memory of early pain

Studies in mice suggest that focusing on genetic changes in macrophages may be beneficial.

Recent research increasingly suggests that the body can retain painful memories of injuries in infancy, including life-saving surgeries, into adolescence.

These early experiences appear to change the way children’s pain response systems develop at a genetic level, leading to more intense responses to pain later in life. This change also appears to be more common in women.

Now, research led by experts at Cincinnati Children’s Hospital has pinpointed how and where the genetic changes that create this lasting memory of pain occur.According to their research, published in the journal cell reportkey changes occur in developing macrophages—one of the main elements of the immune system.

“Our experiments help further confirm how pain memory affects female newborns over longer periods of time. Specifically, our data show that epigenetic changes occur in macrophages after injury early in life (after birth). changes that occur with inherited genetic variants), which in turn can promote a greater pain response to other injuries that occur later in life.

Injury early in life can genetically alter the way the body’s pain response system develops, creating a pain “memory” that affects responses to injury years later, a study suggests. cell report Published by experts at Cincinnati Children’s Hospital.Image credit: Cell Reports and Cincinnati Children’s Hospital

Dr. Adam Dourson, currently at Washington University in St. Louis, is the study’s lead author.

Experiments showed that male mice that experienced similar early-life insults showed the same epigenetic changes but did not maintain the same long-term pain memory as females.Further testing also showed that the change occurred in a file called p75NTRcan be found in human macrophages.

In female mice, pain memory effects were detected for more than 100 days after the initial injury. The incision causes stem cells in the bone marrow to produce macrophages, which are “primed” to respond more strongly to the injury, thereby increasing pain.

For humans, a similar time frame is about 10 to 15 years.

“We were surprised how a single local injury could so dramatically alter the epigenetic/transcriptomic landscape of systemic macrophages,” said Jankowski.

This new understanding of neonatal pain memory highlights fundamental differences between the genetic activity of the still-developing neonatal immune system and the mature system of adults. This means determining how surgeons and care teams adapt rehabilitative care for newborns and baby girls will be complex.

“Simply changing the dosage of painkillers may not be the answer. There is always a balance to be maintained between controlling pain and minimizing the harmful side effects that may arise from existing medications. Instead, our findings suggest the need to develop more specific, targeted treatments method to prevent macrophages from reprogramming in response to injury.

Next step

More research is needed to use this new information to develop therapies to control immune “pain memory.”

In this study, blocking the p75NTR receptor in young mice indeed impaired the ability of macrophages to communicate with sensory neurons and partially prevented prolonged pain-like behavior. However, it is unclear whether a similar approach can be safely used to target human macrophages.

“Emerging technologies appear to be able to specifically block the p75NTR receptor in macrophages, but much more research is needed before this approach is ready for human clinical trials,” Jankowski said.

Reference: “Macrophage memory of early life injury drives neonatal nociceptive priming” by Adam J. Dourson, Adewale O. Fadaka, Anna M. Warshak, Aditi Paranjpe, Benjamin Weinhaus, Luis F. Queme, Megan C. Hofmann, Heather M. Evans, Omer A. Donmez, Carmy Forney, Matthew T. Weirauch, Leah C. Kottyan, Daniel Lucas, George S. Deepe, and Michael P. Jankowski, April 18, 2024 cell report.
DOI: 10.1016/j.celrep.2024.114129

Funding sources for this research include funding from National Institutes of Health (R01NS105715, R01NS113965, F31NS122494, R01HL160614, P30 AR070549; supported by an ARC award from Cincinnati Children’s Hospital and the Leukemia and Lymphoma Society.