Vascular disease ranks as the major cause of limb amputation. Understanding the fundamental biology that controls tissue repair is of critical importance to a wide range of patients suffering from disorders such as trauma or immobilization to diseases like diabetes and cancer.
Currently, researchers from the Emory University School of Medicine have published evidence that by removing the anti-inflammatory cytokine CD163, they were able to boost muscle repair and blood flow after ischemic injury. The implications from this data point to a possible target for therapeutic intervention aimed at enhancing muscle regeneration.
Historically, CD163 has been known for its ability to scavenging excess hemoglobin throughout the body, but its role in muscle repair had not been previously reported. The Emory investigators observed that mice lacking CD163 had significantly increased blood flow and muscle repair, compared to controls, in one leg that contained an injury as a result of blood flow restriction. Interestingly, the researchers found that in the CD163 deficient mice, muscles fibers and blood vessels had substantial growth in the animal’s uninjured leg as well.
“We were astonished,” said senior author Aloke Finn, M.D., assistant professor of medicine in the division of cardiology at Emory University School of Medicine. “Why would something we did, which caused an injury to one leg, help tissue in the other leg regenerate when it wasn't injured in the first place?”
The findings from this study were published recently in Nature Communications through an article entitled “CD163 interacts with TWEAK to regulate tissue regeneration after ischaemic injury.”
Dr. Finn and his colleagues found that macrophages released a soluble form of CD163 in response to injury, which seemed to be responsible for scavenging and counteracting another protein called TWEAK—shown to stimulate muscle cells into proliferation.
The research team observed that in the absence of CD163, TWEAK had a much greater effect and stimulated muscle growth even when it was distant from the point of injury. Conversely, when normal mice are infused with TWEAK, the scientists observed no effect on muscle growth, which they hypothesized, was due to the levels of circulating CD163.
To further prove TWEAK’s essential role in the added repair activity they observed, the investigators took CD163 deficient mice and injected them with an antibody against TWEAK— completely eliminating the added repair activity previously observed.
“I think our results show a specific mechanism by which muscle regeneration takes place,” explained Dr. Finn. “TWEAK can be a pro-regenerative factor, but its effects have to be transient and limited.”
TWEAK has been traditionally thought of as a pro-inflammatory molecule, as it activates a master regulator of inflammation called NF-κB. However, while chronic inflammation is typically bad for muscle growth, when CD163 is absent the presence of increased levels of TWEAK seems to be extremely beneficial for regeneration.
“Ischemic injury is a situation in which TWEAK can stimulate muscle progenitor cells to proliferate,” noted Dr. Finn. “But if you have lots of TWEAK around all the time, the muscle cells don't know when it's time to differentiate and mature.”