If you think of the brain as an advanced programming system, the blood-brain barrier is the "firewall" in this system — it blocks the brain's physical organization from the peripheral circulatory system, preventing harmful substances from entering the central nervous system.
However, when a pathogen infection or systemic inflammation occurs, the "firewall" can also be compromised by "hackers."For example, after sepsis caused by Gram-negative bacteria infection, inflammation will break the blood-brain barrier and aggravate the development of related brain diseases.
What kind of methods did hackers use to break down the firewall?
Recently, Shaofeng team, a member of the Chinese Academy of Sciences and researcher at the Beijing Institute of Life Sciences, and Luo Minmin team, co-director of the Beijing Institute of Brain Science and Brain-like Research, solved this unsolved mystery.
The mysterious "hacker"
When the "firewall" of the blood-brain barrier is damaged, it has a series of dominoic effects that promote or directly lead to the development of a series of central nervous system diseases, such as Alzheimer's disease, multiple sclerosis, and sepsis.
Clinically, some postoperative patients develop sepsis caused by infection.Patients with severe sepsis may even experience damage and failure of multiple organs, including diffuse brain dysfunction.
"Patients with diffuse brain dysfunction, even if they survive, leave behind varying degrees of neurological dysfunction, placing a heavy burden on the individual life and family of the patient.Shao Feng, the corresponding author of the paper, told the China Science Journal.
However, the treatment of diffuse brain dysfunction at home and abroad is not yet a good solution.
Shaofeng said that the destruction of the blood-brain barrier caused by Gram-negative bacteria infection is considered by the scientific community to be an important reason for the development of the disease.Gram-negative bacteria, like hackers, produce a pro-inflammatory factor called lipopolysaccharide, which triggers the destruction of the blood-brain barrier through a specific mechanism, leading to various central nervous system lesions.
But the key molecules behind it and the mechanisms of its cellular biology have long been divided among the scientific community, and the hacking method of destroying the blood-brain barrier, the "firewall", is a "mystery" that needs to be solved.
"There was a previous hypothesis that lipopolysaccharides would be recognized by their extracellular receptor TLR4, inducing the transcription of many pro-inflammatory cytokines, thereby stimulating the blood-brain barrier to be broken.Jiang Wei, co-first author of the paper and Dr. of the Beijing Institute of Life Sciences, said.
But did "hackers" really break the blood-brain barrier with this process?
Over a period of four years, the team conducted in-depth analysis of the specific mechanisms of Gram-negative bacteria destroying the blood-brain barrier through multiple discussions and experiments, reversing previous assumptions.
Using mouse models, they found that lipopolysaccharides destroy the blood-brain barrier by activating their intracellular receptor, Caspase-4/11, which causes GSDMD, a brain endothelial cell, to be activated.Their in vitro cell research also confirmed this.
"A thousand miles from the nest.GSDM protein will 'punch holes' in brain endothelial cells, causing changes in brain endothelial cell permeability, and even causing brain endothelial cells to scorch.Jiang Wei explained to China Science Journal, "This will cause the originally closed blood-brain barrier to be 'broken', causing chaos in the brain, and the substances in the peripheral blood circulation system and the substances in the brain to penetrate each other."”
Build a "firewall"
In order to find out the specific mechanism of the "firewall" being broken, the researchers used "all-out efforts."
"This is a multidisciplinary interdisciplinary study.Jiang Wei told reporters that various comprehensive technologies such as molecular biology, cell biology, mouse genetics, fluorescence imaging technology, and adenovirus technology have been used in research.
One innovation in this study was the establishment of a human-derived CASP4 transgenic mouse model.Wei Chao, PhD, co-first author of the paper, told reporters that this is because the human CASP4 gene is more sensitive to lipopolysaccharides than the mouse Casp11 gene, and can better respond to lower doses of lipopolysaccharide stimulation.
This model not only effectively reveals the mechanism of Gram-negative bacteria destroying the brain-blood barrier, but also provides new ideas for clinical treatment.
"Since over-activation of GSDM can lead to cell coke death, are there negative feedback regulators in the body that control GSDM over-activation?"Is there a corresponding repair mechanism for brain endothelial cells activated by GSDDD?How to design targeted drugs for GSDM to avoid excessive blood-brain barrier destruction?Wei said answering these scientific questions will help to further understand the molecular basis of GSDDD activation in the body, provide deeper theoretical support for building a "strong firewall" to effectively regulate blood-brain barrier permeability.
"Strict", "interesting" and "new", several reviewers of the paper highly praised the study.One of the reviewers wrote: "This study, which uses a variety of advanced techniques to uncover new insights into cell-coking-mediated blood-brain barrier disruption, is a very interesting finding.”
Make the "firewall" more "controllable"
In fact, this study is also important for healthy people."In our daily lives, we should maintain good living habits, exercise steadily, improve immunity, and avoid damage to many body tissues and organs, including the blood-brain barrier, caused by acute infection.""Jiang said.
What's more, researchers say that once the hacker GSDD's "crime" approach is analyzed, people can also "go the other way" – using this mechanism to control the opening and closing of the blood-brain barrier to solve the problem of inefficient drug delivery to the brain.
As a hard core "firewall" of the human brain, the blood-brain barrier, in addition to harmful substances can not enter, some drug molecules can not enter the brain to play a role.Now that the mechanism of blood-brain barrier destruction has been found, it is a step further from the artificial control of this "firewall".
"Once a highly efficient and specific excitatory drug targeting the GSDM protein is designed in the future, controlled opening and closing of the blood-brain barrier will become a reality, which will help drugs deliver and work better," Wei said.