Immune Policing Surges with Decrease in Metalloproteinase Activity

Investigators at the Spanish National Center for Cardiovascular Research (CNIC)—studying the role of matrix metalloproteinases (MMPs) in the recruitment of immune cells and development of atherosclerosis—have just identified a novel function of an MMP that could be exploited for the treatment of some infections and even tumor metastasis. The new study—published today in Nature Communications in an article entitled “MT4-MMP Deficiency Increases Patrolling Monocyte Recruitment to Early Lesions and Accelerates Atherosclerosis”—shows that blockade of the protease MT4-MMP increases the surveillance activity of blood-patrolling monocytes. These cells act like “police patrols” to detect foreign or undesired material in the blood.  

Senior study investigator Alicia Arroyo, Ph.D., who is a senior group leader at CNIC, indicated that the new findings “have possible clinical implications and could contribute to strategies to eliminate foreign or undesired materials from the blood, such as infectious agents or tumor cells.” The study thus “suggests new strategies to combat infection or prevent metastasis, which are currently being evaluated for patent protection.”

Our immune system involves circulating leukocytes with specialized functions. One population consists of inflammatory monocytes that are released rapidly to the circulation in response to injury and generate an immune response at the injury site. But there is another monocyte population tasked with “the surveillance of the blood vessel interior, giving rise to the name blood-patrolling monocytes,” explained Dr. Arroyo. These monocytes rarely migrate to sites of tissue injury, and therefore their role in inflammation is less known.

In the current study, the CNIC team conducted an in-depth analysis of the function of patrolling monocytes in inflammatory disease and the mechanisms that regulate their vascular surveillance activity. As a model, the researchers studied the inflammatory process of atherosclerosis, in which the injury signal is triggered by the deposition of cholesterol—inducing the migration of inflammatory monocytes and, to a lesser extent, patrolling monocytes. Once in the vessel wall, the monocytes differentiate to macrophages, which are specialized in engulfing injurious material, such as the accumulated cholesterol.

“The first things we observed were that early atherosclerotic plaques in mice lacking MT4-MMP (a member of the MMP family) accumulated more macrophages and that atherosclerosis was accelerated when these mice were fed a high-fat diet,” noted lead study investigator Cristina Clemente.

The research team also noted that early lesions in mice lacking MT4-MMP selectively accumulated more patrolling monocytes, whereas inflammatory monocytes were recruited as normal. Ms. Clemente added that “macrophages derived from the patrolling monocytes incorporated more fat and showed better survival than those derived from inflammatory monocytes.” 

However, when the MT4-MMP-deficient mice were treated with the CCR5 inhibitor maraviroc, used to treat patients with human immunodeficiency virus (HIV) infection, the migration of patrolling monocytes to atherosclerotic plaques was blocked, preventing the macrophage accumulation and accelerating atherosclerosis. Thus, blockade of MT4-MMP in early phases promotes atherosclerosis, but at the same time could potentiate the response to treatments to combat infection or prevent metastasis. Still, Dr. Arroyo stressed that “we don't know if this acceleration of atherosclerosis is maintained at later stages, and this is something that will need to be analyzed.”