Abstract
Focal cerebral ischemia can cause blood–brain barrier (BBB) breakdown, which is implicated in neuroinflammation and progression of brain damage. Monocyte chemotactic protein 1–induced protein 1 (MCPIP1) is a newly identified zinc-finger protein that negatively regulates inflammatory signaling pathways. We aimed to evaluate the impact of genetic MCPIP1 deletion on BBB breakdown and expression of BBB-related matrix metalloproteinases (MMPs) and tight junction proteins after cerebral ischemia/reperfusion (I/R) using MCPIP1-deficient (MCPIP1–/–) mice. Transient middle cerebral artery occlusion was induced in the MCPIP1–/– mice and their wild-type littermates for 2 h followed by reperfusion for 24 h. The degree of BBB breakdown was evaluated by injection of fluorescein isothiocyanate (FITC)-dextran. Quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry were performed to compare the expression of MMPs and claudin-5 and zonula occludens-1 (ZO-1). MCPIP1 deficiency in mice resulted in enhanced leakage of FITC-dextran, increased expression of MMP-9/3, and reduced expression of claudin-5 and ZO-1 in the brain compared to that seen in their wild-type littermates subjected to cerebral I/R. These results demonstrate that absence of MCPIP1 exacerbates cerebral I/R-induced BBB disruption by enhancing the expression of MMP-9/3 and the degradation of claudin-5 and ZO-1, providing novel insights into the mechanisms underlying BBB breakdown after cerebral ischemia/reperfusion
Highlights
Ischemic stroke is a devastating neurological disorder with high mortality and limited functional recovery [1]
We recently reported that Monocyte chemoattractant protein-1 (MCP-1) binding to its receptor CCR2 induces a novel zinc-finger protein, named MCP-1-induced protein 1 (MCPIP1) [15], which was further identified as a negative regulator of inflammatory response by inhibition of NF-κB signaling pathway [16]
As we demonstrate in this report, Monocyte chemotactic protein 1–induced protein 1 (MCPIP1)-deficient mice displayed an increased leakage of fluorescein isothiocyanate (FITC)-dextran into the cortical tissue compared to their wild-type littermates following transient focal ischemia
Summary
Ischemic stroke is a devastating neurological disorder with high mortality and limited functional recovery [1]. Activation of MMPs can degrade tight junction proteins claudin-5 and zonula occludens (ZO)-1 [9,10], leading to loss of BBB tight junction integrity, which results in increased paracellular permeability, vasogenic edema, and increased mortality. Both claudin-5 and ZO-1 have been shown to be the essential integral proteins in tight junction, and their levels have been considered as indicators of normal and dysfunctional states of the BBB [4]
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