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Temporal Shifts in MicroRNAs Signify the Inflammatory State of Primary Murine Microglial Cells

Zohar, Keren, Lezmi, Elyad, Reichert, Fanny, Eliyahu, Tsiona, Rotshenker, Shlomo, Weinstock, Marta, Linial, Michal·2025·International Journal of Molecular Sciences
DOI 10.3390/ijms26125677PMC PMC12193602

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Abstract

The primary function of microglia is to maintain brain homeostasis. In neurodegenerative diseases like Alzheimer’s, microglia contribute to neurotoxicity and inflammation. In this study, we exposed neonatal murine primary microglial cultures to stimuli mimicking pathogens, injury, or toxins. Treatment with benzoyl ATP (bzATP) and lipopolysaccharide (LPS) triggered a coordinated increase in interleukin and chemokine expression. We analyzed statistically significant differentially expressed microRNAs (DEMs) at 3 and 8 h post-activation, identifying 33 and 57 DEMs, respectively. Notably, miR-155, miR-132, miR-3473e, miR-222, and miR-146b showed strong temporal regulation, while miR-3963 was sharply downregulated by bzATP. These DEMs regulate inflammatory pathways, including TNFα and NFκB signaling. We also examined the effect of ladostigil, a neuroprotective agent known to reduce oxidative stress and inflammation. At 8 h post-activation, ladostigil induced upregulation of anti-inflammatory miRNAs, such as miR-27a, miR-27b, and miR-23b. Our findings suggest that miRNA profiles reflect microglial responses to inflammatory cues and that ladostigil modulates these responses. This model of controlled microglial activation offers a powerful tool with which to study inflammation in the aging brain and the progression of neurodegenerative diseases.

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Figure 1 Quantitation of TNFα and IL-6 released from primary neonatal murine microglial culture following stimulation. The bars represent the related reduction in the release of TNFα and IL6 from microglia activated by BzATP/LPS. (A) A dose response relative to fully activated culture (100%). Budesonide was added 2 h before BzATP and LPS in the presence of 0.1% BSA. All concentrations of budesonide tested reduced the cytokines significantly (**, p-value < 0.01). Significant differences from the value for TNFα are indicated (# p-value < 0.05). (B) Difference in the reduction in the release of TNFα and IL6 after 8 h (as in (A), with a budesonide concentration of 10–12 M) and at 24 h. The difference between 8 and 24 h was statistically significant (**) with p-value < 0.01. (C) The level of transcripts for Il6, Tnf, and Il1b are tested from the results of RNA-seq analysis. The average TMM and the standard deviations from biological triplicates are shown for each experimental group. The statistical significance with the p-value FDR is very significant for Il6 (FDR 1.1 × 10−18), Tnf (FDR 2 × 10−10), and Il1b (FDR 1.3 × 10−42).
Figure 1 Quantitation of TNFα and IL-6 released from primary neonatal murine microglial culture following stimulation. The bars represent the related reduction in the release of TNFα and IL6 from microglia activated by BzATP/LPS. (A) A dose response relative to fully activated culture (100%). Budesonide was added 2 h before BzATP and LPS in the presence of 0.1% BSA. All concentrations of budesonide tested reduced the cytokines significantly (**, p-value < 0.01). Significant differences from the value for TNFα are indicated (# p-value < 0.05). (B) Difference in the reduction in the release of TNFα and IL6 after 8 h (as in (A), with a budesonide concentration of 10–12 M) and at 24 h. The difference between 8 and 24 h was statistically significant (**) with p-value < 0.01. (C) The level of transcripts for Il6, Tnf, and Il1b are tested from the results of RNA-seq analysis. The average TMM and the standard deviations from biological triplicates are shown for each experimental group. The statistical significance with the p-value FDR is very significant for Il6 (FDR 1.1 × 10−18), Tnf (FDR 2 × 10−10), and Il1b (FDR 1.3 × 10−42).CC BY · PubMed Central
Figure 2 Trends in the gene expression of microglial miRNAs following the activation protocol with BzATP/LPS for 3 h and 8 h. The mapping of 372 miRNAs resulted in 345 uniquely labeled mature miRNAs, defined also by their 5p and 3p arms from the precursor pre-miRNAs. (A) Uniquely identified miRNAs (total 345) are classified into nine modules based on their combined expression trend (up, down, or same, and their combinations). For definitions and thresholds, see details in Supplementary Table S1. The baseline log2(FC) = 0 is shown by the horizontal red line. The miRNAs associated with a distinct short-term kinetics are colored for: up (orange), same (black), and down (blue). The number of miRNAs that belong to each module is indicated. (B) The fold change in the miRNAs that are labeled ‘up-up’. (C) The fold change in the miRNAs that are labeled ‘down-down’. The analysis is based on the data in Supplementary Table S2.
Figure 2 Trends in the gene expression of microglial miRNAs following the activation protocol with BzATP/LPS for 3 h and 8 h. The mapping of 372 miRNAs resulted in 345 uniquely labeled mature miRNAs, defined also by their 5p and 3p arms from the precursor pre-miRNAs. (A) Uniquely identified miRNAs (total 345) are classified into nine modules based on their combined expression trend (up, down, or same, and their combinations). For definitions and thresholds, see details in Supplementary Table S1. The baseline log2(FC) = 0 is shown by the horizontal red line. The miRNAs associated with a distinct short-term kinetics are colored for: up (orange), same (black), and down (blue). The number of miRNAs that belong to each module is indicated. (B) The fold change in the miRNAs that are labeled ‘up-up’. (C) The fold change in the miRNAs that are labeled ‘down-down’. The analysis is based on the data in Supplementary Table S2.CC BY · PubMed Central
Figure 3 A global view of miRNAs’ statistics in microglia culture and time-dependent DEMs following activation. (A) Partition of the 372 identified miRNAs (in %) by their number of miRNAs (# miRNAs, blue) and by their expression level bins (orange, CPM). (B) Scatter plot of log2(FC) and the expression level (CPM). A few miRNAs with maximal FC and high expression levels are indicated. (C) A list of 21 significant DEMs 3 h post-activation with ≥|1.5| folds. (D) A list of 25 significant DEMs 8 h post-activation, with ≥|1.5| folds. The lists are sorted by the fold change. Only miRNAs that were differentially expressed by ≥1.5-fold (upregulated and/or downregulated). Note the larger breadth of the log2(FC) in the data collected from 3 h post-activation relative to 8 h post-activation. For a complete list, see Supplemental Table S6.
Figure 3 A global view of miRNAs’ statistics in microglia culture and time-dependent DEMs following activation. (A) Partition of the 372 identified miRNAs (in %) by their number of miRNAs (# miRNAs, blue) and by their expression level bins (orange, CPM). (B) Scatter plot of log2(FC) and the expression level (CPM). A few miRNAs with maximal FC and high expression levels are indicated. (C) A list of 21 significant DEMs 3 h post-activation with ≥|1.5| folds. (D) A list of 25 significant DEMs 8 h post-activation, with ≥|1.5| folds. The lists are sorted by the fold change. Only miRNAs that were differentially expressed by ≥1.5-fold (upregulated and/or downregulated). Note the larger breadth of the log2(FC) in the data collected from 3 h post-activation relative to 8 h post-activation. For a complete list, see Supplemental Table S6.CC BY · PubMed Central
Figure 4 Dynamics of DEMs following the activation of microglial culture. (A) Venn diagram of the DEMs of two time points (3 h and 8 h). The unique sets that are not shared by both time points are listed. Included are all significant DEMs (FDR ≤ 0.05) and log2(FC) of >|0.33| relative to N.T. cells. The listed names of DEGs are colored as up- and downregulated DEMs by red and green font, respectively. (B) Based on the overlap in A, the representative listed DEMs are those displaying >30% difference in expression between 3 h and 8 h of cell activation. The listed DEMs show ‘up-down’ (left) and ‘up-up’ (right). (C) MA plot of the log2(FC) relative to the CPM (in log) for the 372 identified miRNAs. The temporal DEMs (T-DEMs) are colored by the change expression trends, with the expression of 8 h > 3 h in blue and that of 3 h > 8 h in red. Gray are miRNAs that showed no temporal expression pattern. The change in expression was determined by a threshold of log2(FC) > |0.33| and an FDR q-value < 0.05.
Figure 4 Dynamics of DEMs following the activation of microglial culture. (A) Venn diagram of the DEMs of two time points (3 h and 8 h). The unique sets that are not shared by both time points are listed. Included are all significant DEMs (FDR ≤ 0.05) and log2(FC) of >|0.33| relative to N.T. cells. The listed names of DEGs are colored as up- and downregulated DEMs by red and green font, respectively. (B) Based on the overlap in A, the representative listed DEMs are those displaying >30% difference in expression between 3 h and 8 h of cell activation. The listed DEMs show ‘up-down’ (left) and ‘up-up’ (right). (C) MA plot of the log2(FC) relative to the CPM (in log) for the 372 identified miRNAs. The temporal DEMs (T-DEMs) are colored by the change expression trends, with the expression of 8 h > 3 h in blue and that of 3 h > 8 h in red. Gray are miRNAs that showed no temporal expression pattern. The change in expression was determined by a threshold of log2(FC) > |0.33| and an FDR q-value < 0.05.CC BY · PubMed Central
Figure 5 Network and functional view for T-DEMs and gene targets. (A) miRNet 2.0 view for the 6 identified T-DEMs (blue square) and their experimentally validated targets (pink marker, 244 genes). Genes connecting several miRNAs are labeled. The dominant connection of miR-155-5p is evident. (B) STRING view for a set of 21 protein-coding targets (T-DEGs, Table 1). The protein–protein interaction (PPI) network is significant (PPI enrichment p-value: 0.00986). The enrichment of the gene ontology biological process (GO_BP) of the immune system (GO:0002376) and the regulation of cytokine production (GO:0001817) are colored red and blue, respectively (p-value 3.4 × 10−6). Genes without these GO are not colored. (C) The functional enrichment of the listed genes (21 genes, Table 1) by Reactome pathways. From left to right: the fraction of gene input (red); significant pathways by Reactome are sorted by p-values (blue); and the overlapping genes for each of Reactome’s enriched pathways (orange).
Figure 5 Network and functional view for T-DEMs and gene targets. (A) miRNet 2.0 view for the 6 identified T-DEMs (blue square) and their experimentally validated targets (pink marker, 244 genes). Genes connecting several miRNAs are labeled. The dominant connection of miR-155-5p is evident. (B) STRING view for a set of 21 protein-coding targets (T-DEGs, Table 1). The protein–protein interaction (PPI) network is significant (PPI enrichment p-value: 0.00986). The enrichment of the gene ontology biological process (GO_BP) of the immune system (GO:0002376) and the regulation of cytokine production (GO:0001817) are colored red and blue, respectively (p-value 3.4 × 10−6). Genes without these GO are not colored. (C) The functional enrichment of the listed genes (21 genes, Table 1) by Reactome pathways. From left to right: the fraction of gene input (red); significant pathways by Reactome are sorted by p-values (blue); and the overlapping genes for each of Reactome’s enriched pathways (orange).CC BY · PubMed Central
Figure 6 The effect of ladogtigil on miRNA expression. MA plots of the log2(FC) relative to the CPM (in log) for the 372 identified miRNAs in a fully activated setting (bzATP/LPS). (A) shows 3 h post-activation relative to N.T. Note that none of the miRNA was marked as significantly up (red) or down (blue). (B) shows 8 h post-activation relative to N.T. The miRNAs that were upregulated by ladostigil are marked in red font. The gray color is miRNAs that showed no significant expression change. The change in expression was determined by a threshold of log2(FC) > |0.33| and an FDR q-value < 0.05. The dashed lines mark stable expressions.
Figure 6 The effect of ladogtigil on miRNA expression. MA plots of the log2(FC) relative to the CPM (in log) for the 372 identified miRNAs in a fully activated setting (bzATP/LPS). (A) shows 3 h post-activation relative to N.T. Note that none of the miRNA was marked as significantly up (red) or down (blue). (B) shows 8 h post-activation relative to N.T. The miRNAs that were upregulated by ladostigil are marked in red font. The gray color is miRNAs that showed no significant expression change. The change in expression was determined by a threshold of log2(FC) > |0.33| and an FDR q-value < 0.05. The dashed lines mark stable expressions.CC BY · PubMed Central

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Metadata

Authors
Zohar, K., Lezmi, E., Reichert, F., Eliyahu, T., Rotshenker, S., Weinstock, M., & Linial, M.
Affiliations
  • Department of Biological Chemistry, Institute of Life Science, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
  • Department of Genetics, Institute of Life Science, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
  • Department of Medical Neurobiology, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91121, Israel
  • Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
ORCID
Linial, Michal
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2025-06-13
Volume
26
Issue
12
Pages
5677
ISSN
1422-0067
DOI
10.3390/ijms26125677
PMC
PMC12193602
Cited by
1
References
5
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
the Hebrew University of Jerusalem

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