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

Mumps resurgence likely due to waning vaccine-derived immunity

March 21, 2018
A resurgence of mumps in the U.S. among vaccinated young adults appears to be due to waning of vaccine-induced immunity, according to a new analysis from Harvard T.H. Chan School of Public Health. Researchers found that vaccine-derived ...

Western diet depletes artery-protecting immune cells

March 21, 2018
New research from scientists at the La Jolla Institute For Allergy and Immunology shows how a diet high in fat and cholesterol depletes the ranks of artery-protecting immune cells, turning them into promoters of inflammation, ...

Quintupling inhaler medication may not prevent asthma attacks in children

March 19, 2018
Children with mild to moderate asthma do not benefit from a common practice of increasing their inhaled steroids at the first signs of an asthma exacerbation, according to clinical trial results published in The New England ...

How allergens trigger asthma attacks

March 19, 2018
A team of Inserm and CNRS researchers from the Institute of Pharmacology and Structural Biology have identified a protein that acts like a sensor detecting allergens in the respiratory tract that are responsible for asthma ...

Single steroid-bronchodilator treatment for control and rescue improves persistent asthma

March 19, 2018
When it comes to treating teens and adults with persistent asthma, using a single corticosteroid and long-acting bronchodilator treatment for both daily asthma control and for rescue relief during sudden asthma attacks is ...

Obesity and health problems: New research on a safeguard mechanism

March 16, 2018
Obesity and its negative impacts on health - including metabolic syndrome, type-2 diabetes mellitus and cardiovascular complications - are a global pandemic (Taubes, 2009). The worldwide incidence of obesity has more than ...


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.