Researchers at the National Center for Cardiovascular Researchers (CNIC) have discovered that neutrophils acquire different ‘behaviours’ in the blood during inflammatory processes. Specifically, the study, published in Nature, identifies a behavior associated with cardiovascular diseases. Neutrophils are a type of immune cell that help fight infection in the body, being one of the first immune cells to react when microorganisms, such as bacteria or viruses, enter the body. Neutrophils are, therefore, the immune cells that constitute the body’s main line of defense, but they are also capable of causing damage to healthy cells and the cardiovascular system. In fact, “numerous studies have associated the presence of neutrophils in the blood with greater severity and risk of cardiovascular problems,” says the first author of the study, Georgiana Crainiciuc.
Despite this, it is not possible to eliminate these neutrophils to protect the cardiovascular system, since, in the words of the researcher, “it would generate a state of defenselessness against any pathogen that would be counterproductive for the body.”
To solve this problem, the authors sought to identify the specific types of neutrophils responsible for vascular damage. To do this, they analyzed the behavior of the cells using high-resolution intravital microscopy, a type of technology that makes it possible to visualize cells inside the blood capillaries in living animals.
The team designed a highly novel computational system capable of analyzing how cells behave in blood vessels, through simple measurements of changes in cell size, shape and movement. In this way, it was discovered that these immune cells present three patterns of behavior during the course of inflammatory processes, but that only one of them, characterized by a larger size and proximity to the vessel walls, was associated with cardiovascular damage.
The researchers used massive genetic analysis in animal models and were able to identify the molecules responsible for these harmful behaviors of neutrophils. And we have a winner: it is the Fgr . It is responsible for this pathological behavior, and its detection has been key to selecting a highly effective drug to prevent inflammation and cell death after a myocardial infarction. “The idea now is to continue with the necessary trials so that, in the future, this treatment can be used in patients,” says Crainiciuc.
The researchers assure that the study not only represents a great step forward when it comes to treating cardiovascular diseases, it is also a milestone for the methodology developed for the study of immune cells. “Current techniques are capable of analyzing a large number of genes and molecules per cell, which has made it possible to discover the existence of numerous cell populations related to the development of diseases,” says Dr. Miguel Palomino-Segura, co-first author of the study. However, he adds, “our model is unique because it allows us to identify cells, not by their possible genetic profile, but by their type of activity during the disease.”
It is “a completely different approach to the study of immune processes, whose value lies precisely in that it takes advantage of the dynamism of the disease to generate new information”, emphasizes Palomino-Segura.
“A key aspect is that neutrophils are capable of changing their shape, activity and migratory capacity in a matter of seconds. This rapid metamorphosis can only be captured under the microscope”, adds Dr. Andrés Hidalgo, who has led the research.
To extract the full potential of these images, the researchers have collaborated with engineers from the Carlos III University of Madrid, who have developed new artificial vision techniques for measurements in living tissues
The work has also required intense computational development capable of systematically combining and comparing a large amount of data from thousands of cells. “It is a technology that has been applied to other types of data, but this is the first example with in vivo microscopy data and the result has been surprising”, highlights Jon Sicilia, co-author and bioinformatician responsible for the analytical part of the study. draft.
“By analyzing more than 100,000 reconstructions of cell shapes and tracks over time, we obtained individual cell behavior descriptors and used these high-dimensional datasets to build behavioral landscapes. These landscapes recognized the identities of leukocytes in the inflamed skin and trachea, and uncovered a continuum of neutrophil states within the blood vessels,” the authors comment in the Abstract of the article.
With this new methodology, the authors hope that other scientific fields will benefit from their work. “The idea now is to apply it to other scenarios such as infections or tumors, in which immune cells also play a crucial role in the development of the disease,” says Palomino-Segura.
“Conceptually, the demonstration that inflammatory behaviors within vessels are molecularly deterministic rather than stochastic has important implications for targeting vascular inflammation without interfering with antimicrobial immunity,” the article concludes.
The information provided by this work is highly relevant from a therapeutic point of view, since it may allow the development of new treatments to minimize the sequelae caused by myocardial infarctions. The study was published on January 5, 2021 in Nature, under the title Behavioral immune landscapes of inflammation .
Researchers from the Vithas Foundation, the University of Castilla la Mancha, the Singapore Agency for Science and Technology (ASTAR) and Harvard and Baylor Universities have participated in the study. both in the US, among other centers. Likewise, the research has received support from: Ministry of Science and Innovation; La Caixa Foundation; Leducq Foundation; FET-OPEN European Commission; Federation of European Biochemical Societies, and EMBO ALTF.
