Downregulation of CD151 restricts VCAM-1 mediated leukocyte infiltration to reduce neurobiological injuries after experimental stroke.

BACKGROUND: Translational failures in anti-adhesion molecule therapies after stroke reveal the necessity of developing new strategies that not only interrupt leukocyte recruitment but also consider the inhibition of endothelial cell inflammation, verification of therapeutic time window, and normal function maintenance of circulating leukocytes. Our study focused on the potential therapeutic value of CD151 downregulation in improving current anti-adhesion molecule therapies. METHODS: Lentivirus intracerebroventricular administration was conducted to inhibit the CD151 expression and observe its functional influence on neurological injuries and outcomes. Then, immunohistochemistry and myeloperoxidase activity assessment were performed to explore the effects of CD151 expression on neutrophil and monocyte recruitment after rat cerebral ischemia. Primary rat brain microvascular endothelial cells were subjected to oxygen glucose deprivation and reoxygenation to elucidate the underlying working mechanisms between CD151 and VCAM-1. RESULTS: The CD151 downregulation remarkably reduced neurological injuries and improved neurological outcomes, which were accompanied with reduced neutrophil and monocyte infiltration after the CD151 downregulation. The VCAM-1 expression was remarkably decreased among the adhesion molecules on the endothelial cell responsible for neutrophil and monocyte infiltration. The activation of p38 MAPK and NF-κB pathways was restricted after the CD151 downregulation. p38 MAPK and NF-κB inhibitors decreased the VCAM-1 expression, and p38 acted as an upstream regulator of NF-κB. However, CD151 downregulation did not directly influence the neutrophil and monocyte activation. CONCLUSIONS: Overall, CD151 regulated the expression of adhesion molecules. It also played a critical role in suppressing VCAM-1-mediated neutrophil and monocyte infiltration via the p38/NF-κB pathway. This study possibly provided a new basis for improving current anti-adhesion molecule therapies.

Trajectory modeling of endothelial-to-mesenchymal transition reveals galectin-3 as a mediator in pulmonary fibrosis.

The endothelial-to-mesenchymal transition (EndMT) is an important source of fibrotic cells in idiopathic pulmonary fibrosis (IPF). However, how endothelial cells (ECs) are activated and how EndMT impact IPF remain largely elusive. Here, we use unsupervised pseudotemporal analysis to recognize the heterogeneity of ECs and reconstruct EndMT trajectory of bleomycin (BLM)-treated Tie2creER/+;Rosa26tdTomato/+ IPF mice. Genes like C3ar1 and Lgals3 (protein name galectin-3) are highly correlated with the transitional pseudotime, whose expression is gradually upregulated during the fate switch of ECs from quiescence to activation in fibrosis. Inhibition of galectin-3 via siRNA or protein antagonists in mice could alleviate the pathogenesis of IPF and the transition of ECs. With the stimulation of human pulmonary microvascular endothelial cells (HPMECs) by recombinant proteins and/or siRNAs for galectin-3 in vitro, ß-catenin/GSK3ß signaling and its upstream regulator AKT are perturbed, which indicates they mediate the EndMT progress. These results suggest that EndMT is essential to IPF process and provide potential therapeutic targets for vascular remodeling.

CD151 Alleviates Early Blood-Brain Barrier Dysfunction After Experimental Focal Brain Ischemia in Rats.

Preservation of the blood-brain barrier (BBB) function is a potential protective strategy against cerebral ischemic injuries. CD151 has a beneficial effect in maintaining vascular stability and plays a role in pro-angiogenesis. Both vascular stability and angiogenesis can affect BBB function. Therefore, we aimed to examine the action of CD151 in regulating BBB permeability after cerebral ischemic injury in the present study. Using a transient focal cerebral ischemia (tFCI) rat model, we established that CD151 overexpression in the brain mitigated the leakage of endogenous IgG at 6-24 h after tFCI in vivo. Moreover, we found that CD151 can decrease the diffusion of macromolecules through monolayer brain microvessel endothelial cells (BMVECs) after glucose and oxygen deprivation (OGD)-reoxygenation in vitro. Furthermore, overexpression of CD151 in BMVECs suppressed OGD-reoxygenation-induced F-actin formation and RhoA activity. However, while preserving BBB integrity after tFCI, CD151 overexpression did not affect the post-stroke outcomes. Taken together, the present study demonstrated that CD151 overexpression in the brain protects BBB permeability at early phase after tFCI. CD151 may be a potential target for early BBB protection in ischemic stroke.