Down-regulation of circular RNA CDC14A peripherally ameliorates brain injury in acute phase of ischemic stroke

Abstract

Background Inflammation is integral to the pathophysiology of ischemic stroke and a prime target for the development of new stroke therapies. The aim of the present study is to seek out the regulatory mechanism of circCDC14A in neuroinflammatory injury in tMCAO mice. Methods The expression level of circCDC14A in peri-infarct cortex and plasma of mice were detected by qPCR. The localization of circCDC14A in peripheral blood cells and peri-infarct cortex of tMCAO mice were explored by in situ hybridization and immunofluorescence colocalization staining. Lentivirus were microinjected into lateral ventricular of brain or injected into tail vein to interfere with the expression of circCDC14A, thus their effects on behavior, morphology, and molecular biology of tMCAO mice were analyzed. Results The expression of circCDC14A in plasma and peri-infarct cortex of tMCAO mice significantly increased, and circCDC14A was mainly localized in neutrophils peripherally while in astrocytes in peri-infarct cortex centrally. Tail vein injection of lentivirus to interfere with the expression of circCDC14A significantly reduced the infarct volume (P < 0.01) at 72 h after reperfusion and density of activated astrocytes in peri-infarct cortex at 3 days, 5 days and 7 days after tMCAO modeling (all P < 0.0001). Moreover, mNSS (P < 0.0001) and survival rate (P < 0.001) were significantly improved within 7 days in si-circCDC14A group compared to circCon group. Additionally, morphology analysis showed the volume and surface area of each activated astrocytes significantly decreased (P < 0.0001). Quantification analysis measured the percentage of N2 phenotype among infiltrated neutrophils in brain sections and found N2 ratio was significantly higher in si-circCDC14A group compared to circCon group (P < 0.001). Conclusion Knocking down the expression of circCDC14A in peripheral blood cells relieved astrocytes activation in peri-infarct cortex, thereby relieved brain damage in the acute phase of ischemic stroke.

Construction of circRNA-Mediated Immune-Related ceRNA Network and Identification of Circulating circRNAs as Diagnostic Biomarkers in Acute Ischemic Stroke

“…5,33 Recently, several studies found that circRNAs were involved in the pathogenesis of AIS by regulating immunoinflammatory reactions. 17,34,35 The circRNAmediated ceRNA mechanism can be used for the analysis of the molecular basis of various diseases. Hence, constructing a ceRNA network of immune-related circRNAs should help elucidate the inflammatory mechanisms in AIS.…”

“…16 Further study revealed that circCDC14A played a critical role in the regulation of inflammatory reactions during AIS. 17 However, the role of circRNAs serving as ceRNAs in the immune and inflammatory mechanisms of AIS remains less studied. In addition, there are no published studies on the expression of circRNAs in TIA patients.…”

Increased plasma levels of circPTP4A2 and circTLK2 are associated with stroke injury

“…Several recent studies have demonstrated that circRNAs were involved in the pathogenesis of stroke‐related neuroinflammation 30–32 . In a mouse stroke model, knockdown of neutrophil‐derived circCDC14A inhibited astrocyte activation and alleviates neurological damage after cerebral ischemia 31 .…”

Exosomal circBBS2 inhibits ferroptosis by targeting miR‐494 to activate SLC7A11 signaling in ischemic stroke

“…CircRNAs exert critical roles in various pathogenic processes, including ischemic stroke 17 . For example, circCDC14A was highly expressed in the mouse model of ischemic stroke and knockdown of circCDC14A attenuated brain damage during acute ischemic stroke 18 . CircRNA BBS2 (circBBS2, ID: hsa_circ_0039457), originated from the 2‐7 exons of the BBS2 gene, was reported to be down‐regulated in ischemic stroke patients 19 .…”