Endothelial TREM‐1 receptor regulates the blood–brain barrier integrity after intracerebral hemorrhage in mice via SYK/β‐catenin signaling

Abstract Background Intracerebral hemorrhage (ICH) is a high mortality and disability stroke subtype. Destruction of the blood–brain barrier (BBB) is a crucial contributor to brain edema and neurological deficit after ICH. Triggering receptor expressed on myeloid cells 1 (TREM‐1) has been reported to be expressed in endothelial cells, but its role in ICH remains unclear. This study aims to evaluate the role of TREM‐1 on BBB permeability after ICH in mice. Methods Two hundred and forty‐two CD1 mice were used in this study. The ICH model was established by collagenase injection. LP17 was administered intranasally at 2 or 8 h after ICH to inhibit TREM‐1. To explore the underlying mechanism, SYK activation CRISPR was administered intracerebroventricularly with LP17, and Anti‐mouse TREM‐1 rat IgG2a (a specific TREM‐1 agonist) was injected intracerebroventricularly with R406 (a specific SYK inhibitor) intraperitoneally. Neurobehavioral outcome, brain water content, BBB permeability, and protein expression were evaluated. Results The expression level of the TREM‐1 receptor increased rapidly as early as 6 h after ICH, and it was mainly expressed on the endotheliocytes in the neurovascular unit. Early and delayed administration of LP17 significantly decreased brain edema and improved neurobehavioral outcomes at 24 h after ICH. LP17 reduced the BBB permeability by increasing β‐catenin, claudin‐5 and ZO‐1 expression. Furthermore, SYK activation CRISPR abolished the beneficial effect of LP17 on the expression of the above junction molecules. Meanwhile, R406 reversed the impact of the TREM‐1 activator on the downregulation of β‐catenin, claudin‐5 and ZO‐1 expression. Conclusions This study demonstrated that TREM‐1 deteriorated BBB permeability via modulating the expression of interendothelial junction molecules after ICH, and this regulation is partly mediated by the SYK/β‐catenin signaling pathway.