Immune-mediated disruption of the blood-brain barrier after intracerebral hemorrhage: Insights and potential therapeutic targets

Abstract

Aims: Intracerebral hemorrhage (ICH) is a condition that arises due to the rupture of cerebral blood vessels, leading to the flow of blood into the brain tissue. One of the pathological alterations that occurs during an acute ICH is an impairment of the blood-brain barrier (BBB), which leads to severe perihematomal edema and an immune response.

Discussion: A complex interplay between the cells of the BBB, for example, pericytes, astrocytes, and brain endothelial cells, with resident and infiltrating immune cells, such as microglia, monocytes, neutrophils, T lymphocytes, and others accounts for both damaging and protective mechanisms at the BBB following ICH. However, the precise immunological influence of BBB disruption has yet to be richly ascertained, especially at various stages of ICH.

Conclusion: This review summarizes the changes in different cell types and molecular components of the BBB associated with immune-inflammatory responses during ICH. Furthermore, it highlights promising immunoregulatory therapies to protect the integrity of the BBB after ICH. By offering a comprehensive understanding of the mechanisms behind BBB damage linked to cellular and molecular immunoinflammatory responses after ICH, this article aimed to accelerate the identification of potential therapeutic targets and expedite further translational research.

Keywords: blood–brain barrier; cytokines; immune cell; intracerebral hemorrhage; tight junction proteins.

FIGURE 1

The structure of the neurovascular unit in healthy and post‐ICH conditions. The neurovascular unit comprises brain endothelial cells (BECs), basement membrane (BM), pericytes, astrocytes, microglia, and neurons. BECs are the main component of the blood–brain barrier (BBB) and are arranged regularly and tightly connected by tight junction proteins (TJPs). Surrounding the BECs are the BM, pericytes, and astrocyte end feet, which control the passage of cells and molecules into and out of the brain. When an intracerebral hemorrhage (ICH) occurs, the structure of the BBB is compromised, leading to swollen and irregular BECs, reduced expression of TJPs, and shortened and unclear tight junctions, resulting in increased BBB permeability. In addition, pericytes and astrocyte end feet show reduced contact with the BM, and toxic components in the hematoma following ICH activate astrocytes and microglia, damaging neurons.

FIGURE 2

Interactions between immune cells and the BBB after ICH. Detrimental mechanisms: ① Downregulated H2‐kb and upregulated RAE1 and MULT‐1 in BECs activate NK cells, which mediate BECs death. NK cells produce CXCL12, enhancing neutrophil recruitment. ② Astrocytes are activated to reactive astrocytes, releasing CCL5, CCR1, and CCR5, downregulating TJPs to disrupt the integrity of the BBB. ③ Fe²⁺ accumulates in pericytes, which are stimulated by thrombin and release MMP‐9, exacerbating BBB damage. ④ Activated M/M express CCL2 and reduce the expression of TJPs. ⑤ IL‐23, secreted by macrophages, stimulates γδT cells to produce IL‐17, which activates macrophages. ⑥ Neutrophils, neutrophil extracellular traps, Th1 cells and, activated M/M increase pro‐inflammatory factors such as IL‐1β, TNF, and inflammatory damage molecules such as MMPs, iNOS, HMGB1, which exacerbate inflammation and increase BBB permeability. Protective mechanisms: ⑦ LH3 overexpression enhances the integrity of the BM and decreases MMP‐9 expression. ⑧ Immune cells also release a large amount of anti‐inflammatory factors to help repair the BBB. A2‐type astrocytes reduce the expression of IL‐1β and TNF. Treg cells play an immunosuppressive role by inhibiting M/M overactivation. ⑨ IL‐27 production by neutrophils is increased, which has led to an increase in the production of the iron scavengers lactoferrin, promoting the clearance of Fe²⁺ and the integrity of the BBB (Created with BioRender.com).