If we compare the brain to an advanced program system, the blood-brain barrier would be the essential “firewall” of that system. Its role is to isolate the brain’s substantive tissues from the peripheral circulatory system, thereby blocking harmful substances from invading the central nervous system. However, when a pathogen infection or systemic inflammation occurs, this “firewall” might be breached by “hackers.” An example is that Gram-negative bacteria-induced sepsis can destroy the blood-brain barrier and aggravate brain diseases. So, how do these “hackers” crack the “firewall”?
A joint team composed of researchers from the Beijing Institute of Life Sciences, led by Shao Feng, and the Beijing Brain Science and Brain-like Research Institute with co-director Luo Minmin, has unveiled this mystery. For the first time internationally, they have described the molecular and cellular mechanisms of inflammatory damage to the blood-brain barrier caused by Gram-negative bacterial infections. This research has been published in the journal Nature.
Once the blood-brain barrier is damaged, it produces a chain of effects that may promote or directly cause central nervous system diseases, such as Alzheimer’s disease, multiple sclerosis, and sepsis-related encephalopathy. Clinically, some patients may develop sepsis caused by infections after surgery, which can lead to damage or failure of multiple organs, including diffuse brain function disorders. Patients with these brain dysfunction disorders, even after they survive, can still suffer from varying degrees of neurological dysfunction, severely affecting the patients and their families. At present, there is no mature clinical protocol for the treatment of such brain dysfunction, both domestically and internationally.
The scientific community generally believes that the rupture of the blood-brain barrier is caused by Gram-negative bacterial infections, and is considered a major cause in the development of central nervous system diseases. Lipopolysaccharides produced by Gram-negative bacteria, an inflammatory factor, are thought to trigger damage to the blood-brain barrier by a special mechanism, leading to a series of brain pathologies. However, which key molecules and the cellular biological mechanisms behind them are responsible for this process had not yet been clearly answered by previous scientific studies.
After four years of research and multi-experimental verification, Shao Feng’s team, using a mouse model, discovered that lipopolysaccharide acts by activating its intracellular receptor Caspase-4/11, which then activates GSDMD in brain endothelial cells, leading to the loss of blood-brain barrier function. The same was also proved in cell experiments in vitro. GSDMD proteins form pores on brain endothelial cells, altering their permeability, and ultimately even leading to the death of these cells.
In modern medical research, the integrity of the blood-brain barrier is regarded as the key “firewall” for brain health. Once this barrier is breached, it disrupts the brain’s internal environment, leading to uncontrolled infiltration between substances in the surrounding blood and the brain, resulting in a range of health issues.
To reveal the detailed mechanisms causing the blood-brain barrier’s damage, researchers have embarked on a series of interdisciplinary research efforts. The research team applied numerous scientific methods, including molecular biology, cell biology, genetics, and advanced imaging techniques, allowing for an in-depth analysis of this issue.
One of the innovative aspects of the study was the development of a transgenic mouse model carrying the human CASP4 gene. Scientists found that the human CASP4 gene is more sensitive to substances such as lipopolysaccharides, hence this new model could more effectively reveal how exactly the blood-brain barrier is disrupted, while also offering new directions for future clinical treatments.
Another focus of the research is the activation and regulation of the GSDMD protein. Excessive activation of GSDMD can lead to cell death, so researchers are trying to find internal feedback mechanisms to prevent over-activation, as well as cellular repair programs that promote activation. In addition, they are also dedicated to developing targeted drugs for GSDMD to prevent excessive damage to the blood-brain barrier.
The scientific community has highly praised this research. Peer reviewers believe that it not only demonstrates superb scientific research capabilities but also offers a new understanding of the mechanisms behind the disruption of the blood-brain barrier, and they commented that the findings are highly creative and interesting.
This research is of great significance to everyone. In daily life, maintaining a healthy lifestyle, exercising, and enhancing immunity can effectively prevent acute infections from affecting the blood-brain barrier and other vital organs and tissues.
Understanding and controlling the mechanisms of the blood-brain barrier’s opening and closing are equally vital for treating brain diseases, especially when dealing with diseases like gliomas. Grasping the mechanisms of the blood-brain barrier’s disruption brings us closer to the day when we can artificially control its opening and closing. Scientists envision that, if highly efficient and specific drugs targeting GSDMD protein can be designed, it might be possible to achieve controllable opening and closing of the blood-brain barrier, which would help drugs enter the brain more smoothly and exert therapeutic effects.
