miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A

Neelima Gupta, Shweta Jadhav, Kai-Leng Tan, Genevieve Saw, Karthik Babu Mallilankaraman, S Thameem Dheen, Neelima Gupta, Shweta Jadhav, Kai-Leng Tan, Genevieve Saw, Karthik Babu Mallilankaraman, S Thameem Dheen

Abstract

Microglia, the innate immune effector cells of the mammalian central nervous system (CNS), are involved in the development, homeostasis, and pathology of CNS. Microglia become activated in response to various insults and injuries and protect the CNS by phagocytosing the invading pathogens, dead neurons, and other cellular debris. Recent studies have demonstrated that the epigenetic mechanisms ensure the coordinated regulation of genes involved in microglial activation. In this study, we performed a microRNA (miRNA) microarray in activated primary microglia derived from rat pup's brain and identified differentially expressed miRNAs targeting key genes involved in cell survival, apoptosis, and inflammatory responses. Interestingly, miR-142-3p, one of the highly up-regulated miRNAs in microglia upon lipopolysaccharide (LPS)-mediated activation, compared to untreated primary microglia cells was predicted to target Ca2+/calmodulin dependent kinase 2a (CAMK2A). Further, luciferase reporter assay confirmed that miR-142-3p targets the 3'UTR of Camk2a. CAMK2A has been implicated in regulating the expression of brain-derived neurotrophic factor (BDNF) and long-term potentiation (LTP), a cellular mechanism underlying memory and learning. Given this, this study further focused on understanding the miR-142-3p mediated regulation of the CAMK2A-BDNF pathway via Cyclic AMP-responsive element-binding protein (CREB) in activated microglia. The results revealed that CAMK2A was downregulated in activated microglia, suggesting an inverse relationship between miR-142-3p and Camk2a in activated microglia. Overexpression of miR-142-3p in microglia was found to decrease the expression of CAMK2A and subsequently BDNF through regulation of CREB phosphorylation. Functional analysis through shRNA-mediated stable knockdown of CAMK2A in microglia confirmed that the regulation of BDNF by miR-142-3p is via CAMK2A. Overall, this study provides a database of differentially expressed miRNAs in activated primary microglia and reveals that microglial miR-142-3p regulates the CAMK2A-CREB-BDNF pathway which is involved in synaptic plasticity.

Keywords: Ca2+/calmodulin dependent kinase 2a (CAMK2A); brain-derived neurotrophic factor (BDNF); microRNA; microRNA-142 (miR-142-3p/5p); microarray; microglia BV2; rodent primary microglia.

Copyright © 2020 Gupta, Jadhav, Tan, Saw, Mallilankaraman and Dheen.

Figures

Figure 1
Figure 1
Global miRNA expression profiling shows the differential expression of miRNAs in activated microglia. (A) Heat map generated from microRNA microarray shows the result of differential miRNAs expression in control vs. lipopolysaccharide (LPS)-treated primary microglia. Each column represents a biological sample while each row represents a miRNA. The color scale represents the relative expression level of each miRNA in each sample as compared to the reference channel. Red color indicates an expression that is higher than the reference channel, while green color indicates an expression that is below the reference. (B) Volcano plot illustrating the relation between the logarithm of the p-values and the log fold change of miRNAs differentially expressed in control and LPS-activated microglia. The top selected miRNAs are marked with annotation on the plot and tabulated on the right. (C) Quantitative RT-PCR analysis of few differentially expressed miRNAs found in miRNA microarray in Control vs. LPS activated primary microglia. Results are represented as fold change for untreated controls. Statistical analysis was carried out using ANOVA with post hoc Tukey test. Data represented as mean ± SD, (n = 5), ***p < 0.001; **p < 0.01; *p < 0.05.
Figure 2
Figure 2
Ingenuity pathway analysis (IPA) analysis of differentially expressed miRNAs in activated primary microglia compared to control microglial cells. (A,B) IPA showing up- (red) and down-regulation (green) of miRNAs and their target gene networks such as NF-κB (A) and Akt (B) in LPS-activated primary microglial cells when compared to control.
Figure 3
Figure 3
miR-142-3p/5p upregulates in activated microglia and targets CAMK2A. (A) Histogram depicts a significant upregulation of miR-142-3p and miR-142-5p in activated microglia upon LPS treatment for 6 h. Data represented as mean ± SD, (n = 5), Students t-test, *p < 0.05. (B) Bioinformatics analysis predicted that miR-142-3p and miR-142-5p putatively target 3′UTR of Camk2a. The seed region and the target site type have been highlighted (TargetScan and Miranda software was used to predict miRNA targets. Image acquired from http://www.microrna.org/). (C) Histogram depicting a significant decrease in mRNA expression levels of Camk2a in activated microglia upon LPS treatment for 6 h, suggesting an inverse relationship between miR-142-3p/5p and its target gene, Camk2a. Data represented as mean ± SD, (n = 4), Students t-test, ***p < 0.001.
Figure 4
Figure 4
Downregulation of CAMK2A-BDNF pathway proteins in LPS-activated primary microglia. (A) Immunoblots of CAMK2A (50 kDa), phosphorylation of CREB (pCREB; 43 kDa), BDNF (15 kDa) in LPS activated primary microglia show significant downregulation. Total cyclic AMP-responsive element-binding protein (CREB) and β-actin show no difference between control and activated microglia. (B) Histogram shows the significant downregulation of CAMK2A, pCREB, and BDNF in microglia treated with LPS for 6 h. Immunoblot data has been quantified and normalized to β-actin. Phospho-CREB was then normalized to total CREB. Data represented as mean ± SD, (n = 3), Students t-test, *p < 0.05. (C) Immunofluorescence analysis shows that CAMK2A (red) expression appears to be decreased in primary microglia treated with LPS for 6 h when compared to controls. (D) Immunofluorescence analysis shows that BDNF (red) expression also appears to be decreased in primary microglia treated with LPS for 6 h when compared to controls. Lectin (green) used as microglial markers. Nuclei are stained with DAPI (blue), (n = 3), Scale bars = 20 μm.
Figure 5
Figure 5
miR-142-3p targets CAMK2A and regulates the CAMK2A-BDNF pathway in microglia. (A–C) Immunoblot and densitometry analysis shows that overexpression of mir-142-3p mimics suppresses the protein expression levels of CAMK2A and BDNF in BV2 microglia significantly. However, overexpression of miR-142-5p did not suppress CAMK2A protein expression levels. Data represented as mean ± SD, (n = 3), Students t-test, **p < 0.01; *p < 0.05. (D–F) Immunoblot and densitometry quantification shows that overexpression of mir-142-3p inhibitors in BV2 microglia leads to an increase in the protein expression levels of CAMK2A and BDNF, suggesting an inverse relationship between miR-142-3p and CAMK2A. Immunoblot data has been quantified and normalized to β-actin. Data represented as mean ± SD, (n = 3), Students t-test, *p < 0.05. (G) The histogram shows a significant decrease in the luciferase activity in BV2 cells co-transfected with miR-142-3p mimics and luciferase vector as compared to cells co-transfected with negative control miRNA and luciferase vector, indicating that miR-142-3p targets CAMK2A. Data represented as mean ± SD, (n = 3), Students t-test, **p < 0.01.
Figure 6
Figure 6
shRNA mediated knockdown of CAMK2A suppresses the CAMK2A-BDNF pathway in microglia. (A) Quantitative RT-PCR results show a significant decrease in the mRNA levels of Camk2a in BV2 microglia following the shRNA-mediated knockdown of CAMK2A (shCAMK2A). Data represented as mean ± SD, (n = 4), Students t-test, ***p < 0.001. (B) Immunoblot shows that the shRNA mediated knockdown of CAMK2A leads to the downregulation of BDNF via the downregulation of pCREB in BV2 microglia when compared to negative control plasmid (pLKO) transfected microglial cells. (C) The histogram shows the significant downregulation of CAMK2A, pCREB, and BDNF in shCAMK2A microglia, compared to negative control plasmids (pLKO) transfected microglial cells. Immunoblot data has been quantified and normalized to β-actin. Phospho-CREB was then normalized to total CREB. Data represented as mean ± SD, (n = 3), Students t-test, ***p < 0.001; **p < 0.01; *p < 0.05. (D) Immunofluorescence analysis shows that CAMK2A (red) expression appears to be decreased in shCAMK2A microglial cells compared to negative control plasmids (pLKO) transfected microglial cells. (E) Immunofluorescence analysis shows that BDNF (red) expression appears to be decreased in shCAMK2A microglial cells compared to negative control plasmids (pLKO) transfected microglial cells. Lectin (green) used as microglial markers. Nuclei are stained with DAPI (blue), (n = 3), Scale bars = 20 μm.
Figure 7
Figure 7
miR-142-3p epigenetically regulates the CAMK2A-BDNF pathway in microglia. In the activated microglia, miR-142-3p was upregulated, leading to suppression of its target, CAMK2A protein expression, which eventually downregulates the level of BDNF through decreased pCREB (red arrow indicates upregulation and green arrow indicates downregulation). This illustration suggests that under pathological conditions, the CAMK2A-BDNF pathway which is known to be involved in learning and memory is epigenetically regulated in activated microglia.

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