Blocking a protein could improve the effectiveness of intravascular cellular 'policing'

March 2, 2018, Centro Nacional de Investigaciones Cardiovasculares
Image shows blood-patrolling monocytes (red) adhering to inflamed endothelium (green) in the inner curvature of the aortic arch of a mouse with incipient atherosclerosis. Credit: CNIC

Researchers at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), led by Dr. Alicia G. Arroyo, have identified a function of a protease that could be targeted for the treatment of some infections and even tumor metastasis. The study, published today in Nature Communications shows that blockade of the protease MT4-MMP increases the surveillance activity of a type of white blood cell in the circulation, the blood-patrolling monocytes. These cells act like 'police patrols' to detect foreign or undesired material in the blood. The findings, according to Dr. Alicia G Arroyo, "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.

The immune system circulates leukocytes () with specialized functions. One population consists of that are released rapidly 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. These monocytes rarely migrate to sites of tissue injury, and therefore, their role in inflammation is less known.

Now, in the Nature Communications study, the CNIC team reports 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 atherosclerosis, the injury signal is triggered by the deposition of cholesterol, which induces 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.

First author Cristina Clemente says, "The first things we observed were that early in mice lacking MT4-MMP accumulated more macrophages and that atherosclerosis was accelerated when these mice were fed a high-fat diet."

The researcher also observed that early lesions in mice lacking MT4-MMP selectively accumulated more patrolling monocytes, whereas inflammatory monocytes were recruited as normal. Clemente says, "Macrophages derived from the patrolling monocytes incorporated more fat and showed better survival than those derived from inflammatory monocytes."

But when the MT4-MMP-deficient mice were treated with the CCR5 inhibitor Maraviroc, used to treat patients with HIV, the migration of patrolling monocytes to atherosclerotic plaques was blocked, preventing the macrophage accumulation and accelerated 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. However, Dr. Arroyo says, "We don't know if this acceleration of atherosclerosis is maintained at later stages, and this is something that will need to be analyzed.

The authors also identified that MT4-MMP can cut integrin αM, a crucial leukocyte adhesion receptor. Thus, in the absence of the protease, this receptor accumulates on the surface of patrolling monocytes. Through collaboration with CNIC colleague Cristina Rus, the research team used intravital microscopy to visualize the surveillance activity of patrolling monocytes, detecting increased numbers of these cells in inflamed vessels of mice lacking MT4-MMP.

Explore further: Study reveals how kidney disease happens

More information: Cristina Clemente et al, MT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis, Nature Communications (2018). DOI: 10.1038/s41467-018-03351-4

Related Stories

Study reveals how kidney disease happens

February 22, 2018
Monash researchers have solved a mystery, revealing how certain immune cells work together to instigate autoimmune kidney disease.

No platelets, no immune response

August 1, 2016
When a virus attacks our organism, an inflammation appears on the affected area which triggers off the process of immune defence within our body. White blood cells (such as neutrophils and inflammatory monocytes) move quickly ...

Macrophage proliferation appears to drive progression of atherosclerosis

August 11, 2013
New insights into the development of vulnerable atherosclerotic plaques could lead to better treatment or prevention of heart attacks and strokes. In a report being published online in Nature Medicine, researchers at the ...

Scientists flip molecular switches to distinguish related immune cells

November 1, 2016
The cornerstone of genetics is the loss-of-function experiment. In short, this means that to figure out what exactly gene X is doing in a tissue of interest—be it developing brain cells or a pancreatic tumor—you somehow ...

Discovery of the monocytes that secrete a pro-inflammatory protein

August 10, 2017
Different populations of white blood cells secrete different levels of IL-1β, a pro-inflammatory protein that normally helps the body fight off infection and injury, but may also trigger autoimmune disease and inflammatory ...

Recommended for you

Gene variant found in brain complicit in MS onset

December 18, 2018
Multiple sclerosis (MS) is an autoimmune disease affecting the function of the central nervous system. Up to now, most of the 230 genetic variants associated with the disease have been linked to changes in immune cells. However, ...

Gut microbiome regulates the intestinal immune system, researchers find

December 18, 2018
Scientist have long known that bacteria in the intestines, also known as the microbiome, perform a variety of useful functions for their hosts, such as breaking down dietary fiber in the digestive process and making vitamins ...

How a single faulty gene can lead to lupus

December 18, 2018
A research team at the Academy of Immunology and Microbiology, within the Institute for Basic Science (IBS) & Pohang University of Science and Technology (POSTECH) in South Korea has discovered the role of a key gene involved ...

Metal chemotherapy drugs boost the impact of immunotherapy in cancer

December 18, 2018
Due to their powerful tumour-killing effect, metal-based chemotherapies are frequently used in cancer treatment. However, it was hitherto assumed that they damaged the immune system, because of their cytotoxic (cell-damaging) ...

Clues to chronic fatigue syndrome in overactive immune response

December 18, 2018
New research from King's College London finds that an exaggerated immune response can trigger long-lasting fatigue, potentially explaining how chronic fatigue syndrome (CFS) begins. The study is the most in-depth biological ...

Protein police keep the immune system in check

December 17, 2018
Our immune systems defend our bodies against dangerous invaders and help clean up when damage is done. But if our bold protectors are left unsupervised, they sometimes do their jobs too well and end up harming healthy tissues. ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.