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Blood-brain barrier; Neuroinflammation; Immune system; Multiple sclerosis; Autoimmune encephalitis; Neurovascular unit; Tight junctions; Inflammation

Introduction

The blood-brain barrier (BBB) is a specialized interface formed by brain endothelial cells, pericytes, astrocytes, and the basement membrane, collectively known as the neurovascular unit (NVU). This highly selective barrier tightly regulates the movement of ions, molecules, and cells between the systemic circulation and the CNS, maintaining a stable microenvironment essential for neuronal function. In neuroinflammatory diseases, this barrier function is compromised, allowing for the infiltration of peripheral immune cells into the CNS, which contributes to chronic inflammation and neuronal damage. This review examines the intricate interplay between BBB dysfunction and immune system activity in the pathogenesis of various neuroinflammatory conditions, including multiple sclerosis (MS), autoimmune encephalitis, and other related disorders.  

Results

The BBB's integrity is maintained by several key structures and mechanisms. Tight junctions between endothelial cells are the primary barrier, restricting paracellular diffusion of molecules. Transporters and efflux pumps regulate the transcellular transport of specific molecules. The basement membrane provides structural support, and pericytes and astrocytes contribute to BBB regulation through signaling pathways and structural interactions. In neuroinflammatory diseases, several factors contribute to BBB breakdown. Inflammation itself plays a crucial role. Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IFN-γ, released by activated immune cells, can directly disrupt tight junctions and increase BBB permeability [1]. Matrix metalloproteinases (MMPs), enzymes that degrade extracellular matrix components, are also upregulated in neuroinflammation and contribute to BBB breakdown [2]. Immune cell infiltration further exacerbates BBB dysfunction. Activated T cells and B cells can release pro-inflammatory mediators and directly interact with endothelial cells, disrupting tight junctions and increasing permeability [3]. In MS, for example, autoreactive T cells recognizing myelin antigens cross the compromised BBB and initiate an inflammatory cascade within the CNS, leading to demyelination and axonal damage. In autoimmune encephalitis, autoantibodies targeting neuronal antigens can also contribute to BBB dysfunction by activating complement and triggering inflammatory responses at the NVU [4]. The breakdown of the BBB has significant consequences for CNS function. It allows for the entry of peripheral immune cells, such as lymphocytes and monocytes, into the brain parenchyma, where they can contribute to ongoing inflammation and neuronal damage. It also allows for the leakage of serum proteins, including albumin and immunoglobulins, into the CNS, which can further exacerbate inflammation and disrupt neuronal function. Studies have shown that BBB dysfunction precedes clinical symptoms in some neuroinflammatory diseases, suggesting that it plays a crucial role in disease initiation and progression [5]. The degree of BBB disruption can also correlate with disease severity and clinical outcomes. Recent research has focused on identifying specific molecular targets involved in BBB dysfunction in neuroinflammatory diseases. For example, adhesion molecules on endothelial cells, such as ICAM-1 and VCAM-1, mediate the adhesion and transmigration of immune cells across the BBB [6]. Targeting these adhesion molecules has shown promise in preclinical studies as a potential therapeutic strategy. Furthermore, research has explored the role of specific signaling pathways, such as the NF-κB pathway, in regulating BBB permeability in neuroinflammation [7]. Inhibiting these pathways may offer a therapeutic approach to preserving BBB integrity. The NVU, composed of the BBB and surrounding cells, is now recognized as a key player in neuroinflammation. Interactions between endothelial cells, pericytes, astrocytes, and neurons within the NVU contribute to both BBB regulation and inflammatory responses [8]. For example, astrocytes can release factors that regulate BBB permeability and also contribute to inflammation through the release of cytokines. Furthermore, recent studies have highlighted the role of non-coding RNAs, such as microRNAs, in regulating BBB function and inflammation in neuroinflammatory diseases [9]. These microRNAs can modulate the expression of genes involved in tight junction integrity, inflammation, and immune cell trafficking. Finally, emerging evidence points to the influence of the gut microbiome on BBB integrity and neuroinflammation [10]. Dysbiosis, an imbalance in the gut microbiota, can lead to increased systemic inflammation, which can subsequently impact BBB function and contribute to neuroinflammation. 

Discussion

The findings presented here emphasize the critical role of BBB dysfunction in the pathogenesis of neuroinflammatory diseases. The breakdown of this barrier allows for the infiltration of peripheral immune cells and inflammatory mediators into the CNS, contributing to chronic inflammation and neuronal damage. Understanding the complex interplay between the BBB and the immune system is crucial for developing effective therapeutic strategies. Targeting specific molecules and pathways involved in BBB dysfunction, such as tight junctions, adhesion molecules, and inflammatory mediators, holds promise for preserving BBB integrity and reducing neuroinflammation.

Conclusion

The BBB plays a vital role in maintaining CNS homeostasis and protecting the brain from immune cell infiltration. In neuroinflammatory diseases, BBB dysfunction is a key pathological feature that contributes to disease initiation and progression. Further research is needed to fully elucidate the complex mechanisms involved in BBB breakdown and to develop targeted therapeutic strategies to preserve BBB integrity and reduce neuroinflammation in these debilitating conditions.

1. Muscaritoli M, Bossola M, Aversa Z, Bellantone R and Rossi Fanelli F (2006) “.” Eur J Cancer 42:31–41.

        , ,

2. Laviano A, Meguid M M, Inui A, Muscaritoli A and Rossi-Fanelli F (2005 ) “Therapy insight: cancer anorexia-cachexia syndrome: when all you can eat is yourself.”Nat Clin Pract Oncol 2:158–165.

ÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌý , ,

3. Fearon K C, Voss A C, Hustead D S (2006) “.”Am J Clin Nutr 83:1345–1350.

ÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌý , ,

4. Molfino A, Logorelli F, Citro G (2011) “.”Nutr Cancer63: 295–299.

ÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌý , ,

5. Laviano A, Gleason J R, Meguid M M ,Yang C, Cangiano Z (2000 ) “.”J Investig Med 48:40–48.

ÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌý ,

6. Pappalardo G, Almeida A, Ravasco P (2015) “.”Nutr 31:549–555.

, ,

7. Makarenko I G, Meguid M M, Gatto L (2005) “.”Neurosci Lett 383:322–327.

ÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌý , ,

8. Fearon K C, Voss A C, Hustead D S (2006) “.”Am J Clin Nutr 83:1345–1350.

, ,

9. Molfino A, Logorelli F, Citro G (2011) “.”Nutr Cancer63: 295–299.

ÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌý , ,

10. Laviano A, Gleason J R, Meguid M M ,Yang C, Cangiano Z (2000 ) “.”J Investig Med 48:40–48.

,