Scientists at the Gladstone Institutes have discovered how immune cells in the heart trigger scarring, a process known as fibrosis, which plays a key role in the progression of many diseases.
This finding not only explains the complex link between inflammation and fibrosis in the heart but also suggests that existing drugs could be repurposed to target this damaging cycle in other organs as well.
Fibrosis happens when the body’s natural wound-healing process goes overboard, leading to the buildup of scar tissue.
While scarring is beneficial in small doses to heal injuries like cuts, too much can stiffen and weaken major organs like the heart, liver, kidneys, and lungs, eventually causing organ failure.
This type of fibrosis becomes particularly common with aging and in people suffering from chronic diseases.
The research team, led by Gladstone Assistant Investigator Michael Alexanian, Ph.D., discovered that immune cells and fibroblasts—cells responsible for forming scar tissue—communicate more intricately than previously thought.
Their study, published in Nature, revealed that blocking specific signals between these cells can prevent scarring in the heart. Remarkably, some of these signals are already targeted by drugs currently used to treat other conditions, offering hope for new therapies.
“Inflammation and fibrosis are closely linked and play crucial roles in worsening heart failure, which affects 25 million people worldwide,” said Deepak Srivastava, MD, the study’s senior author and president of Gladstone.
“By finding new ways to interrupt these processes, we could significantly improve the lives of millions of patients.”
How Inflammation Fuels Fibrosis
Scientists have known for a while that inflammation and fibrosis often appear together in aging or diseased organs. However, the exact chain of events between immune cells causing inflammation and fibroblasts forming scar tissue wasn’t fully understood until now.
To investigate, the researchers studied mice with heart disease. They examined how both immune cells and fibroblasts changed as the disease progressed and treated the mice with a BET inhibitor, a drug known to stop fibrosis but with many side effects in other tissues.
This allowed them to explore how the treatment affected heart cells and gather insights into developing more precise therapies.
They found that during heart disease, immune cells called macrophages turned on a set of genes that trigger inflammation. When treated with the drug, these inflammation-related genes were turned off, suggesting that the drug was reducing both inflammation and fibrosis at once.
The team then discovered a direct link between macrophages and fibroblasts. When the heart is under stress, the researchers observed that a regulatory gene called Brd4 is activated in macrophages, causing them to release a signaling molecule known as IL-1β.
This molecule interacts with nearby fibroblasts, triggering them to switch on a gene called MEOX1, which drives fibrosis.
New Therapeutic Possibilities
According to co-author Arun Padmanabhan, MD, Ph.D., “We pinpointed where inflammation starts in macrophages and how it triggers fibroblasts. By understanding this chain of events, we can find ways to intervene earlier and potentially stop fibrosis in patients.”
The researchers showed that blocking different steps in this macrophage-fibroblast pathway could reduce fibrosis in the hearts of mice with heart disease.
This breakthrough is particularly promising because drugs that inhibit IL-1β already exist for treating inflammation-related conditions like cancer, rheumatoid arthritis, and diabetes.
However, further studies are needed to confirm whether these drugs can effectively stop fibrosis in the heart or other organs.
“Now that we’ve mapped out these signals, we can work on creating drugs that specifically target fibrosis without interfering with the immune system’s ability to fight infections,” said Alexanian, who is also a professor at the University of California, San Francisco (UCSF).
The Bigger Picture
The study’s findings highlight the importance of understanding the interaction between inflammation and fibrosis in the progression of many diseases, not just in the heart.
For example, fibrosis plays a major role in liver cirrhosis, chronic kidney disease, and lung conditions like pulmonary fibrosis. By targeting these newly identified pathways, researchers hope to develop treatments that can tackle fibrosis across multiple organs.
While this research is still in its early stages, the discovery of how immune cells signal fibroblasts to form scar tissue could lead to more precise and effective therapies for fibrotic diseases.
These insights offer hope for millions of patients dealing with chronic diseases and age-related organ damage.
In short, the study opens new avenues to target fibrosis at its root cause by blocking harmful signals between immune cells and fibroblasts.
This not only sheds light on how inflammation leads to scarring but also offers a promising path for developing treatments that could one day transform the way we treat heart disease and other fibrotic conditions.
If you care about heart health, please read studies that vitamin K helps cut heart disease risk by a third, and a year of exercise reversed worrisome heart failure.
For more information about heart health, please see recent studies about supplements that could help prevent heart disease, stroke, and results showing this food ingredient may strongly increase heart disease death risk.
The research findings can be found in Nature.
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