Title : Pro-inflammatory cytokine-mediated modulation of blood-brain barrier integrity: Mechanisms and therapeutic opportunities
Abstract:
Background: Neuroinflammation is a hallmark of neurological disorders including Alzheimer’s disease, stroke, multiple sclerosis, and traumatic brain injury. Central to this pathology is the disruption of the blood-brain barrier (BBB), predominantly orchestrated by pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. These cytokines intricately modulate endothelial tight junctions and vascular signalling pathways, resulting in altered BBB permeability that paradoxically opens avenues for targeted drug delivery. Despite extensive research on BBB dysfunction, a focused, systematic synthesis elucidating cytokine-specific molecular mechanisms and their translational therapeutic potential remains conspicuously absent.
Methods: This systematic review was conducted in accordance with PRISMA guidelines. A comprehensive search of PubMed, Scopus, and Web of Science was performed to identify peer- reviewed articles published between January 2010 and May 2025. Inclusion criteria encompassed studies investigating the effects of pro-inflammatory cytokines on BBB integrity in both in vitro and in vivo models, with exclusion of non-English and non-primary research articles. Risk of bias and methodological quality were assessed using the SYRCLE tool.
Results: From 2,900 studies screened, 90 met the inclusion criteria. Cytokine-induced BBB disruptionwas onsistently mediated through NF-κB signalling, oxidative stress, and tight junction downregulation (e.g., claudin-5, occludin, ZO-1). A novel mechanism identified was glycocalyx degradation, which compounds permeability. For example, TNFα (10?ng/mL) and IL1β (50?ng/mL) increased albumin and dextran permeability ~2.5-fold within 6 hours. Based on these insights, the “Cytokine-Primed Therapeutic Gate” framework was developed to redefine how inflammatory signalling can be harnessed to precisely modulate BBB permeability, thereby having potential to revolutionize CNS drug delivery strategies.
Conclusion: Our synthesis reveals cytokine-driven BBB disruption as a context-dependent phenomenon that simultaneously accelerates neuropathology and unveils therapeutic windows. Harnessing this duality demands innovative strategies to spatiotemporally modulate cytokine activity, balancing barrier restoration with controlled permeability enhancement for optimized CNS drug delivery. The proposed framework integrates inflammatory signalling with therapeutic design, advancing both neuropathologic understanding and treatment innovation.
