Scientists Pinpoint Macrophages that Fight Chronic Inflammation

Inflammation is our immune system’s response to injury or infection. However, if it persists for an extended period, it can damage tissues and contribute to the development of diseases. Research has shown that chronic low-grade inflammation—known as inflammaging—worsens as we age; however, the exact cause of this inflammation is still not fully understood.

Now, new research published in Nature Aging has identified how the nervous system might contribute.

Earlier work led by Vishwa Deep Dixit, DVM, PhD, at Yale School of Medicine (YSM) revealed that macrophages—immune cells best known for engulfing pathogens—display unusually high levels of neurotransmitters, chemical messengers typically associated with nerve cells, when they are within fat tissue.

“When we found that these macrophages in fat tissue contained such high levels of neurotransmitters, we began to wonder, what are they doing there, and do they change with age?” says Dixit, senior author of the new study and Waldemar Von Zedtwitz Professor of Pathology at YSM.

The answer lies with a specialized group of macrophages, known as nerve-associated macrophages (NAMs), which reside on the fat tissue and help regulate fat metabolism and control age-related inflammation.

In their new study, Dixit and his team found that these NAMs decline as we grow older while another macrophage subset emerges. Their findings shed light on how immune and nervous system interactions shape metabolism and inflammation across the lifespan.

Macrophages play a critical role in initiating, sustaining, and resolving inflammation. While research often classifies them into just two subsets, the discovery of immune cells with nerve-like properties residing in the fat tissue challenged the team to find out more.

“We did not know anything about these macrophages, so we had a lot of groundwork to do,” says Claire Leveau, a postdoctoral fellow in the Dixit lab and one of the co-authors of the study.

Focusing on the visceral adipose tissue—the deep tissue that surrounds vital organs—the team imaged macrophages in both young (2-month-old) and aged (22-month-old) male and female mice.

To tell apart macrophages that circulate in the blood from those living in fat tissue, the researchers tagged the circulating ones and left the resident ones unmarked. They then isolated the resident cells and read their RNA, which shows which genes are switched on. This allowed them to sort the fat-residing macrophages into 13 distinct groups, including NAMs and another they dubbed age-associated macrophages (AAMs).

“We found 13 different macrophages, all with different cellular machinery,” says Dixit. “And there was a bonus of discovering cells we didn’t know existed!”

The AAMs were found exclusively in aged mice. They expressed high levels of inflammatory markers and genes linked to inflammaging, indicating that they may drive age-related inflammation.

“We are still unclear about the exact roles of these subsets, but their discovery is surely exciting,” Leveau says.

Age is the leading factor contributing to the development of diseases, including cancer, cardiovascular diseases and neurodegeneration. With age, the body’s homeostatic cells—those essential for maintaining proper function, including the NAMs identified by Dixit’s team—decline rapidly.

Normally, certain nerves communicate with macrophages, but that process falters with age. When the team eliminated NAMs in older animals, they observed that tissue function deteriorated further because the nerve–immune connection broke down.

Specifically, the loss of these macrophages impaired the breakdown of fat and greatly increased inflammaging.

“Now that we understand how these macrophages change with age, the next step is figuring out how to preserve the healthy ones and prevent harmful, age-associated types from emerging,” Dixit says. “If we can do that, aging will continue with time, but the decline in tissue function could be reduced.”

With the discovery of several macrophage subsets, the team hopes these findings will eventually pave the way for new medical interventions.

“This discovery is truly just a stepping stone towards understanding the complex biology of aging and the complex intercommunication between nerves and macrophages,” Dixit says.