Long Noncoding RNA H19 Promotes Neuroinflammation in Ischemic Stroke by Driving Histone Deacetylase 1–Dependent M1 Microglial Polarization

Abstract

Background and Purpose-Long noncoding RNA H19 is repressed after birth, but can be induced by hypoxia. We aim to investigate the impact on and underlying mechanism of H19 induction after ischemic stroke. Methods-Circulating H19 levels in stroke patients and mice subjected to middle cerebral artery occlusion were assessed using real-time polymerase chain reaction. H19 siRNA and histone deacetylase 1 (HDAC1) plasmid were used to knock down H19 and overexpress HDAC1, respectively. Microglial polarization and ischemic outcomes were assessed in middle cerebral artery occlusion mice and BV2 microglial cells subjected to oxygen-glucose deprivation. Results-Circulating H19 levels were significantly higher in stroke patients compared with healthy controls, indicating high diagnostic sensitivity and specificity. Moreover, plasma H19 levels showed a positive correlation with National Institute of Health Stroke Scale score and tumor necrosis factor-α levels. After middle cerebral artery occlusion in mice, H19 levels increased in plasma, white blood cells, and brain. Intracerebroventricular injection of H19 siRNA reduced infarct volume and brain edema, decreased tumor necrosis factor-α and interleukin-1β levels in brain tissue and plasma, and increased plasma interleukin-10 concentrations 24 hours poststroke. Additionally, H19 knockdown attenuated brain tissue loss and neurological deficits 14 days poststroke. BV2 cell-based experiments showed that H19 knockdown blocked oxygenglucose deprivation-driven M1 microglial polarization, decreased production of tumor necrosis factor-α and CD11b, and increased the expression of Arg-1 and CD206. Furthermore, H19 knockdown reversed oxygen-glucose deprivationinduced upregulation of HDAC1 and downregulation of acetyl-histone H3 and acetyl-histone H4. In contrast, HDAC1 overexpression negated the effects of H19 knockdown. Conclusions-Our findings indicate that H19 promotes neuroinflammation by driving HDAC1-dependent M1 microglial polarization, suggesting a novel H19-based diagnosis and therapy for ischemic stroke. (Stroke. 2017;48:2211-2221.

The correlation of long non‐coding RNA intersectin 1‐2 with disease risk, disease severity, inflammation, and prognosis of acute ischemic stroke

“…According to the previous studies, several lncRNAs act as enhancers of inflammatory responses in AIS by activating inflammation‐related pathways such as NF‐κB pathway, TRL pathway, and JAK/STAT pathway . For instance, increased lncRNA H19 expression is associated with impaired neurological function and increased TNF‐α level in AIS animal models . Antisense non‐coding RNA in the cyclin‐dependent kinase inhibitor 4 locus (ANRIL), an antisense lncRNA co‐clustered with p15/CDKN2B‐p16/CDKN2A‐p14/ARF, is overexpressed in cerebral infarction rat models and plays a pro‐inflammatory role by activating NF‐κB pathway .…”

“…[19][20][21][22] For instance, increased lncRNA H19 expression is associated with impaired neurological function and increased TNF-α level in AIS animal models. 23 Antisense non-coding RNA in the cyclin-dependent kinase inhibitor 4 locus (ANRIL), an antisense lncRNA co-clustered with p15/CDKN2B-p16/CDKN2A-p14/ ARF, is overexpressed in cerebral infarction rat models and plays a pro-inflammatory role by activating NF-κB pathway. 24 Likewise, ln-cRNA Gm4419 could activate NF-κB pathway and contributes to cell damage in oxygen-glucose-deprived cerebral microglial cells.…”

LncRNA RMST activates TAK1‐mediated NF‐κB signaling and promotes activation of microglial cells via competitively binding with hnRNPK

“…Recently, we have demonstrated that RMST silencing protected neurons against OGD‐induced apoptosis in vitro, decreased cerebral infarction size and neuronal apoptosis and improved neurological function in MCAO mice . Accumulating evidence demonstrated that lncRNAs participate in the progression of neurological disorders through regulating microglial polarization, including H19, tumor suppressor candidate 7 (TUSC7), small nucleolar RNA host gene 1 (SNHG1) . However, to date, the association between ischemic stroke‐induced microglial activation and RMST upregulation has not been studied.…”

Long noncoding RNA HOTTIP alleviates oxygen‐glucose deprivation‐induced neuronal injury via modulating miR‐143/hexokinase 2 pathway

“…13,14,16,17 Although the function of HOTTIP has been widely studied in several tumors, its role in ischemic stroke remains elusive. 13,14,16,17 Although the function of HOTTIP has been widely studied in several tumors, its role in ischemic stroke remains elusive.…”

“…During ischemic attacks and acute glucose deprivation, glycolytic metabolism in the brain is impaired, leading to neuron death. 17 HOXA transcript at the distal tip (HOTTIP) is a newly identified lncRNA located at the 5′ end of the HOXA gene cluster. 13,14 Recently, studies have discovered that a series of lncRNAs are abnormally expressed and play vital roles in ischemic stroke.…”