Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation

Abstract

Background and Purpose Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147, also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses. Methods Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with anti-CD147 function blocking antibody (αCD147) or isotype control antibody. Blood-brain barrier permeability, thrombus formation, and microvascular patency were assessed 24h after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia. Results CD147 expression was rapidly increased in ischemic brain endothelium after tMCAO. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after tMCAO. The neuroprotective effects were associated with 1) prevented BBB damage, 2) decreased intravascular fibrin- and platelet- deposition, which in turn reduced thrombosis and increased cerebral perfusion, and 3) reduced brain inflammatory cell infiltration. The underlying mechanism may include reduced nuclear factor NF-κB activation, matrix metalloproteinase-9 (MMP-9) activity, and plasminogen activator inhibitor-1 (PAI-1) expression in brain microvascular endothelial cells. Conclusions Inhibition of CD147 ameliorates acute ischemic stroke by reducing thrombo-inflammation. CD147 might represent a novel and promising therapeutic target for ischemic stroke and possibly other thrombo-inflammatory disorders.

CD147 promotes progression of head and neck squamous cell carcinoma via NF‐kappa B signaling

“…The activation of NF‐kappa B induced the formation of the IKK (IκB kinase) protein complex and some protein regulate the complex as IKK interactors, such as Hsp70, Hsp90. And some NF‐kappa B targeted genes promote tumor growth, invasion and metastasis, such as MMP‐9 and IL‐6 . There are reports shown that CD147 promoted the expression of MMP‐9, which might be a mechanism that CD147 promoted tumor progression and invasion in HNSCC via regulating NF‐kappa B signaling .…”

“…We focused on NF‐kappa B pathway for three reasons. First, many previous studies demonstrated the molecular link between CD147 and NF‐kappa B pathway . Second, NF‐kappa B target several genes that are important for the inflammatory response, cell proliferation, adhesion, interaction with the microenvironment, as well as tumor growth and metastasis .…”

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

“…A variety of danger signals together with pro-inflammatory cytokines and chemokines drive the initial response. Endothelial cells are activated with loss of tight junctions and integrity of the BBB, which is further weakened by MMPs (released by neutrophils, pericytes, pro-inflammatory M1 resident/infiltrating myeloid cells, and endothelial cells), as well as by reactive oxygen species, and oxidative stress (Jin et al, 2017; Petrovic-Djergovic et al, 2016; Rayasam et al, 2017; Takata et al, 2011). This creates a route for entry of immune cells into the brain parenchyma along with solutes and water that result in interstitial inflammation and edema that further damages neuronal tissue.…”

“…Moreover, downstream microvascular thrombosis likely contributes to incomplete reperfusion in ~25% of patients who undergo successful thrombolysis (Alexandrov et al, 2004; De Silva et al, 2009). CD147 (cluster of differentiations 147) was recently identified as a potential target for ischemic stroke injury linking microvascular inflammation and thrombosis (Jin et al, 2017). This type I transmembrane glycoprotein is expressed by key players in both processes (platelets, leukocytes, and endothelial cells) and is upregulated in the brain after cerebral ischemia.…”

“…This type I transmembrane glycoprotein is expressed by key players in both processes (platelets, leukocytes, and endothelial cells) and is upregulated in the brain after cerebral ischemia. In a mouse model of ischemic stroke (transient MCAO/tMCAO), post-treatment with an anti-CD147 function-blocking antibody (αCD147) preserved BBB integrity, decreased inflammatory cell infiltrates, and reduced microvascular thrombosis, which was associated with reduced intravascular fibrin and platelet accumulation (Jin et al, 2017). At the level of the endothelial cell, treatment with αCD147 reduced activity of MMP9, a known disruptor of the BBB, as well as activation/expression of key modulators of inflammatory and thrombotic responses after ischemic stroke.…”