Frontaging neurosci - New insights into neurodegeneration: inflammatory cytokines and the blood-brain barrier

Neurodegeneration after neuroinflammation, such as those caused by Alzheimer's disease (AD), stroke, multiple sclerosis (MS), and post-traumatic brain injury (TBI), is often associated with high mortality and morbidity and permanent cognitive dysfunction, which places a heavy financial burden
on families and society.
Early diagnosis and cure of these diseases remains a challenge
in clinical research and treatment.

Recent studies have found that these diseases share a key pathological feature, the disruption
of the blood-brain barrier (BBB).
The main cause that destroys the BBB is uncontrolled inflammation after injury or disease, and major cytokines from systemic inflammation can also cause conditions
as serious as neurological disease or injury.
This review discusses the physiological structure of BBBs, inflammatory factor cytokines and the mechanisms
by which they destroy BBBs.
Effects of inflammation on the blood-brain barrier

During neurological disease or injury, immune cells within the brain secrete pro-inflammatory cytokines, the structure of the BBB tends to be looser, and the PC that regulates transcytosis and the TJ that regulates the bycellular pathway are disrupted (Figure 1C).

。 Immune cells from outside the brain, such as T cells, specifically target adhesion molecules on the BBB, specifically intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and subsequently, immune cells enter the central nervous system through membrane endothelial cells, mediated by cell membrane acute-like invagination cluster adhesion molecules through endocytosis, and are expressed
by neutrophils at an early stage through matrix metalloproteins (MMPs) through the stromal membrane 。 Cytokines secreted by immune cells disrupt TJs at a later stage to open the cell bypass pathway, allowing more immune cells to cross the BBB (Figure 1).

Figure 1: Factors secreted by immune cells and their effects on BBB and CNS

Effects of TNFα on the blood-brain barrier and neurodegeneration

TNFα is a major homotrimeric transmembrane protein belonging to the TNF/TNFR ligand/receptor superfamily and plays an important role
in neuroinflammation and blood-brain barrier permeability.
When neuroinflammation is uncontrolled, sustained TNFα secretion alters BBB permeability and worsens neurological disease or injury
.
Microglia-induced TNFα interacts with TNFR-1 to disrupt TJs and lead to BMECs necrosis, allowing toxins and pathogens to enter the CNS
.
In addition, it was found that TNFα can reduce the expression of Cldn5 by activating the NF-κB signaling pathway, thereby disrupting the TJ structure
.

Effects of IL-1β on the blood-brain barrier and neurodegeneration

IL-1β destroys the BBB in two ways: First, IL-1β can activate ACs to destroy the BBB and exacerbate the progression of
neurological disorders or damage.
Recent studies have shown that IL-1β induces the expression of hypoxia-inducible factor-1 (HIF-1) and its gene target, vascular endothelial growth factor-A (VEGF-A) in human astrocytes, thereby inducing cell breakdown of BBB and exacerbating CNS degeneration
.
Second, IL-1β promotes the secretion of other pro-inflammatory cytokines (IL-6 and TNFα), thereby disrupting the paracellular BBB pathway
.
Figure 2 Effects of IL-1β on BBB and neurodegeneration

Effects of other latent cytokines on the blood-brain barrier and neurodegeneration

Inflammation is controlled by a complex network of various pro-inflammatory cytokines and receptors (Table 1).

However, the exact cytokines and receptors involved in neuroinflammation and how they act through signaling pathways remain unclear
.
In addition to major cytokines such as TNFα, IL-1β, IL-6 and their receptors, other cytokines also play an important role in neuroinflammation and neurodegeneration, which may provide some promising new targets for clinical applications in the treatment of neurological diseases and injuries
.
Table 1 Inflammatory factors and their role in BBB

Effects of primary neurological disorders or systemic inflammatory cytokines on the blood-brain barrier and central nervous system

In primary neurological diseases such as AD, MS, stroke, and TBI, inflammatory cytokines play an important role
in promoting disease healing or worsening disease progression in the early or late stages, respectively.
However, in neurological disorders, damage to the central nervous system may lead to a decrease in inflammation control, leading to inflammatory disorders
.
In this case, abnormal expression of inflammatory cytokines can lead to worsening neurological diseases, leading to neurodegeneration, which may also provide an effective target for future clinical treatments
.

conclusion

The main factors that disrupt the BBB to induce neurodegeneration are three inflammatory cytokines: TNFα, IL-1β, and IL-6
.
As inflammatory networks, these cytokines bound to their special receptors can similarly disrupt the TJs and TEERS of the BBB without causing any damage to the AJs, promoting apoptosis of ACs, and recruiting leukocytes into the BBB, directly or indirectly inducing neurodegeneration
.
Several other cytokines, including HMGB1 and IL-10, also play an important role
in BBB.

Individuals with acute or chronic non-encephalic disease account for a large proportion of the world's patients, and there are few treatments that protect against the BBB
.
Aging makes BBB more susceptible to damage by inflammatory cytokines, and damage to BBB can easily recruit more immune cells and cytokines into the brain parenchyma, which in turn induces neurodegeneration
.
Therefore, whether preventing BBB destruction caused by non-brain injury and disease will delay the onset of neurodegeneration and improve its progression requires future large-scale research
.