One enzyme, two roles: Study of immune cells leads to promising questions related to cancer, obesity and beyond

One enzyme, two roles: Study of immune cells leads to promising questions related to cancer, obesity and beyond

Scientists at the Life Sciences Institute (LSI) have illuminated a previously unexplored phase in the complicated life of immune cells, explaining how a single enzyme performs multiple, seemingly unrelated functions at different times in the cell. Their findings add insight to chronic inflammation, particularly as it relates to obesity, atherosclerosis and other conditions, as well as point to new areas of research examining the role that same enzyme plays in cancer cells.
 
“In a car, each part has a function, and if you remove a part, you’d expect the car not to work as well,” said LSI faculty member Stephen Weiss, the senior author on a study recently published in Genes & Development  detailing their findings on new roles for a membrane-anchored protease, termed MT1-MMP. “But in cells, a single part can have many, many functions in the machine and removing one part can interfere with some functions while enhancing others.”
 
The researchers focused on the macrophage, a large, slow-moving type of immune cell that spends most of its time patrolling tissues. But when an organism is wounded, the macrophage makes its way, along with other immune cells, to the site of the injury to both fight infection and orchestrate tissue repair.  To do so, macrophages must move through the fibrous extracellular matrix, a sort of fabric of collagen molecules that surrounds and supports all cells in the body.
 
Scientists have long- assumed that the macrophages cut a path through the spongy matrix using the same protease, or “molecular scissors,” that cancer tumors use to spread, but the recent Genes & Development paper, authored by Weiss, his former post-doc, Ryoko Shimizu-Hirota (lead author), and fellow LSI faculty member, Ivan Maillard along with a team of other collaborators, debunked that theory—and, to the researchers’ surprise, further illuminated the molecular underpinnings  of  the immune response and how that process might be controlled.
 
Earlier, Weiss and colleagues published a series of papers in Cell, Genes & Development, PNAS and the Journal of Cell Biology that narrowed down the potential candidates for the “molecular scissors” used by cancerous tumors to traverse tissue barriers to MTI-MMP. Upon the realization that other types of peripatetic cells – like macrophages - produced MT1-MMP, too, scientists concluded that these other cells likewise used the same “molecular scissors” to travel through the matter between cells.
 
Weiss didn’t agree. “I doubted that conclusion for a simple reason,” he said. “The immune cells that are your first line of defense, neutrophils, have to move quickly through the tissues, and they move really, really fast. And they don’t make MT1-MMP at all. So, wait a minute—how important can our molecular scissors be for moving immune cells through extracellular matrix?”
 
Ryoko Shimizu-Hirota was a post-doctoral fellow from Japan working in Weiss’ lab at the LSI . In 2009, she began a series of experiments using transgenic mice where the gene for MT1-MMP had been disrupted and comparing them to normal mice. In about a year, she found that immune cells in MT1-MMP-deleted mice that no longer expressed the “molecular scissors” were able to move through tissues just as well as normal cells.   
 
It was a significant finding, and Weiss wanted to publish the work as it challenged current dogma. But Shimizu-Hirota had another question she wanted to answer first: If the macrophage is not using MT1-MMP as scissors to cut their way through tissues, what was it using it for? “By hook or by crook - hopefully, not “crook”, she was going to find this out,” Weiss said.
 
One clue was that gene expression analysis of macrophages isolated from mice that lacked MT1-MMP indicated an exaggerated immune response that promoted inflammation. But what would a “pair of scissors” attached to the outer membrane of a cell have to do with regulating immune responses controlled  from within the nucleus?
 
What the researchers found was that the protease was performing a completely novel function in an entirely different part of a cell, a finding that illuminates more of the narrative of the life of an immune cell in the body.
 
“It’s an unusually complicated story,” Weiss said.
 
When the body is wounded, macrophages rush to the site of the assault and begin to kill the invading bacteria entering through the damaged skin. How exactly they travel to the site is still unknown, but they don’t get there using MT1-MMP “scissors.” First, they generate a family of inflammatory molecules that help destroy the invading microbes. Only after the “bugs” are destroyed do macrophages mobilize their MT1-MMP molecular scissors to prune away damaged extracellular matrix molecules to allow for healing. At the same time, however, a portion of the MT1-MMP unexpectedly moves from the cell surface into the nucleus of the cell to initiate a series of signaling events that damper the further generation of  inflammatory molecules that are no longer required during tissue repair.
 
“It makes a kind of sense,” Weiss said. “You could argue that immune cells not only have a ‘killer’ role, they also have a ‘repair’ role. When the macrophage makes the scissors to begin to clip away damage cells, it’s also signaling, ‘Guys, I’m done. The bugs are gone. It’s time to stop fighting the infection and repair the wound.’”
 
When the MT1-MMP was removed, however, the signal to stop making inflammatory molecules was never sent, and the macrophages just continued performing their anti-bacteria, pro-inflammatory work, a state that could lead to chronic inflammation.
 
In newer work, the mechanisms outlined in their recent paper also appear to operate in other immune cell populations involved in host defense and antigen processing as well as blood vessels and even in cancer cells. As therapeutics are currently under development for blocking MT1-MMP in human patients, the researchers conclude that examination of how the enzyme moves from the cell surface to the nucleus and the role it plays in this compartment will provide new insights into the control of the inflammatory response, angiogenesis and even the regulation of the metastatic cascade.

"MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function."

—Mar 29, 2012