Immune Cells in the BBB Disruption After Acute Ischemic Stroke: Targets for Immune Therapy?

Abstract

Blood-Brain Barrier (BBB) disruption is an important pathophysiological process of acute ischemic stroke (AIS), resulting in devastating malignant brain edema and hemorrhagic transformation. The rapid activation of immune cells plays a critical role in BBB disruption after ischemic stroke. Infiltrating blood-borne immune cells (neutrophils, monocytes, and T lymphocytes) increase BBB permeability, as they cause microvascular disorder and secrete inflammation-associated molecules. In contrast, they promote BBB repair and angiogenesis in the latter phase of ischemic stroke. The profound immunological effects of cerebral immune cells (microglia, astrocytes, and pericytes) on BBB disruption have been underestimated in ischemic stroke. Post-stroke microglia and astrocytes can adopt both an M1/A1 or M2/A2 phenotype, which influence BBB integrity differently. However, whether pericytes acquire microglia phenotype and exert immunological effects on the BBB remains controversial. Thus, better understanding the inflammatory mechanism underlying BBB disruption can lead to the identification of more promising biological targets to develop treatments that minimize the onset of life-threatening complications and to improve existing treatments in patients. However, early attempts to inhibit the infiltration of circulating immune cells into the brain by blocking adhesion molecules, that were successful in experimental stroke failed in clinical trials. Therefore, new immunoregulatory therapeutic strategies for acute ischemic stroke are desperately warranted. Herein, we highlight the role of circulating and cerebral immune cells in BBB disruption and the crosstalk between them following acute ischemic stroke. Using a robust theoretical background, we discuss potential and effective immunotherapeutic targets to regulate BBB permeability after acute ischemic stroke.

Keywords: blood-brain barrier; immune cells; immune therapy; inflammation; ischemic stroke.

Figure 1

Temporal profile of peripheral immune cells accumulation after stroke onset based on experimental data. Neutrophil accumulation in the ischemic hemisphere increased significantly after 3 hours, reaching maximum accumulation after 24 hours, followed by a steady dissipation over 7 days. Monocyte counts in the ipsilateral hemisphere robustly increased after 1 day, peaked after 3 - 7 days, and then returned to baseline levels after 14 days. Lymphocytes extravasate into the injured hemisphere in smaller counts and longer persistence compared to the former two immune cells. The accumulation of T cells in the ischemic hemisphere significantly increased as early as 24 hours after AIS, peaked at 3 days, and persisted for 1 month.

Figure 2

Schematic representation of cerebral and peripheral immune cells regulating BBB integrity during early and later phases of ischemic stroke. Infiltrated neutrophils produce proteases (MMPs, proteinase 3, and elastase), lipocalin-2, NET, microvesicles, cytokines, and chemokines to destroy the BBB structure. M1-type monocytes secret cytokines and chemokines to degrade TJs. Perivascular microglia phagocyte ECs, which directly lead to endothelial dysfunction and BBB disintegration. In addition, M1 microglia disrupt BBB integrity through the production and secretion of pro-inflammatory factors (IL-1α, IL-1β, IL-6, TNF-α, IFN-γ, and CCL2), MMP9, and VEGF. A1 astrocytes directly exert deleterious effects on BBB through increasing VEGF, cytokines (IL-1β, IL-6, and TNF-α), chemokines (CCL2 and CCL5), MMP, and LCN-2. However, in the recovery phase of AIS, these immune cells contribute to inflammation resolution and BBB re-establishment. N2 neutrophils promote engulfment of neutrophils by macrophages and inflammation resolution. Monocyte-derived M2 macrophages facilitate the expression of collagen IV and efferocytosis. Microglia directly protect BBB integrity through the secretion of IL-10 and TGF-β. A2 astrocytes are capable of secreting IL-2, IL-10, and TGF-β to accelerate inflammation resolution.

Figure 3

Schematic representation of T lymphocytes homeostasis disorder regulating BBB integrity in ischemic stroke. DAMP and chemokines are released from the ischemic brain via impaired BBB. Acute infarction in the brain can induce microbiota dysbiosis in the gut. Microbiota dysbiosis abolishes the ability of Dendritic cells (DC) to drive the Treg differentiation and promotes the power of DC to induce γδT cell differentiation. The disturbed balance between pro-inflammatory subsets and anti-inflammatory subsets contributes to BBB disruption during ischemic stroke. Th1 and Th17 may degrade TJs and destroy BBB integrity through secreting IFN-γ, IL-17, and IL-21 in the acute phase. CD8⁺T cells potentiate the ischemic stroke progression by two main methods: one is granzyme-b and FasL induced cytotoxicity through FasL-PDPK1 pathway and the other is TNF-α and IFN-γ. Treg suppresses the overactivation of resident microglia, infiltrated T cells, and neutrophils, and decrease pro-inflammatory factors (TNF-α, IFN-γ, IL-1β) levels mainly through the action of IL-10 and TGF-β.