Absence of MCP-induced Protein 1 Enhances Blood–Brain Barrier Breakdown after Experimental Stroke in Mice

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

Tetramethylpyrazine Preserves the Integrity of Blood-Brain Barrier Associated With Upregulation of MCPIP1 in a Murine Model of Focal Ischemic Stroke

“…In addition, we showed that genetic suppression of MCPIP1 abolishes TMP-mediated cell protection, upregulates TNF-α expression, and exacerbates OGD-induced cell death in cultured neurons in vitro . The results obtained from our study are consistent with a recent study showing that genetic knockout of MCPIP1 exacerbates ischemia-induced BBB breakdown and ischemic brain injury ( Jin et al, 2013 ; Jin et al, 2019b ). Other proinflammatory cytokines, like IL-1β, IL-6, and MCP-1, also contribute to the BBB breakdown and subsequent progression of neuron death and dysfunction ( Dimitrijevic et al, 2006 ; Strecker et al, 2011 ; Yao and Tsirka, 2014 ; Amantea et al, 2015 ; Esenwa and Elkind, 2016 ).…”

Zinc Finger Proteins in Neuro-Related Diseases Progression

“…MCPIP1 also functions as a RNase promoting inflammatory mRNA degradation ( Musson et al, 2020 ). In the absence of MCPIP1, the expression of matrix metalloproteinase (which destroys extracellular matrix and destroys the BBB) and the expression of Claudin-5 (integrin of TJs) is decreased, which aggravates BBB destruction ( Jin et al, 2019 ). In addition to MCPIP1-mediated inflammatory responses, ZEB1 (C2H2 type) in microglia after ischemic stroke can reduce neutrophils infiltration into ischemic brain by reducing the production of C-X-C motif ligand 1 (CXCL1) in astrocytes (CXCL1 is a chemokine that mainly absorbed neutrophil), thereby alleviating nerve injury ( Li et al, 2018 ).…”

let-7 microRNAs: Their Role in Cerebral and Cardiovascular Diseases, Inflammation, Cancer, and Their Regulation

“…Another study has shown that TRAIL-R2 is one of the most powerful biomarkers for predicting long-term mortality in many diseases, such as diabetes, heart failure, myocardial infarction, smoking, and hypercholesterolemia [153]. MCPIP1 has recently been shown to negatively regulate inflammatory responses after ischemic stroke, to enhance blood-brain barrier integrity, and to be neuroprotective [154]. Additionally, RBM3 has recently been shown to be neuroprotective and positively correlate with good ischemic stroke outcomes [155].…”