Transcriptome analysis of alcohol-treated microglia reveals downregulation of beta amyloid phagocytosis.

paper Cited Public

Authors: Kalinin, Sergey; González-Prieto, Marta; Scheiblich, Hannah; Lisi, Lucia; Kusumo, Handojo; Heneka, Michael T; Madrigal, Jose L M; Pandey, Subhash C; Feinstein, Douglas L
Year: 2018
Journal: Journal of neuroinflammation
PMID: 29759078
DOI: 10.1186/s12974-018-1184-7
PMCID: PMC5952855

Fig. 1

Alcohol increases microglial inflammatory activation. Primary rat microglia were incubated overnight with nothing (control), with TII to induce an inflammatory response, with 75 mM ethanol (Alc), or with TII and ethanol (Alc and TII). The next day, nitrite production was measured using Griess reagent. The data is the mean ± sem of n = 6–15 replicates done in 3 independent studies. *P < 0.05; ***P < 0.0001; one-way ANOVA, Tukey’s post hoc analysis

Fig. 2

Validation of RNAseq results. Reverse transcriptase quantitative PCR (qPCR) was used to measure mRNA levels of the indicated Alc-DEs. qPCR was carried out in samples from microglia incubated for 24 h with nothing (control, n = 3) or 75 mM ethanol (n = 3), and results normalized to values measured for β-actin in the same samples. The y-axis shows the ratio of the average mRNA level measured in the ethanol versus the control samples (filled bars) and is plotted next to the fold-difference calculated from RNAseq data (open bars). For qPCR results, *P < 0.05; #P < 0.10 control vs alcohol. For the RNAseq data, all DEs were found significantly different using Deseq2

Fig. 3

Overlap of identified DEs. A Venn diagram illustrating overlap of Alc-DEs (n = 312; orange, regions 1, 2, 4, and 5), TII-DEs (n = 3082; green, regions 2, 3, 5, and 6) and AlcTII-DEs (n = 3552; blue, regions 4, 5, 6, and 7). The full list of the DEs in each group is provided in Additional file 1: Tables S1-S4

Fig. 4

Alcohol reduces amyloid beta phagocytosis in rat microglia. Primary rat microglia were incubated overnight with a nothing (control), b 75 mM ethanol, c TII, or d 75 mM ethanol and TII. The next day, the cells were assayed by flow cytometry for phagocytosis of FAM-labeled oligomeric Aβ1–42. e Average internalized FAM fluorescence per cell. Data is from 3 different batches of microglial cells totaling 9197 (controls), 8976 (alcohol), 24,588 (TII), and 28,773 (Alc * TII) events. *P < 0.005 versus control cells, one-way ANOVA, Tukey’s post hoc analysis

#	Section	Preview
0	Background	Microglial activation occurs in a variety of neurological conditions and diseases, and increasing…
1	Background	receptors [1, 2, 7–13]. In many cases, the effects of alcohol were shown to involve activation of…
2	Background	Despite the above studies that focused on specific genes or categories of genes, there are few…
3	Background	While microglial activation and increased pro-inflammatory cytokine and chemokine expression can…
4	Background	In the current study, we evaluated the acute effects of alcohol on inflammatory responses in primary…
5	Methods — Primary microglial cells	All studies with animals were approved by the UIC Institutional Animal Care and Use Committee.…
6	Methods — Alcohol and cytokine treatment	Microglia were exposed to ethanol in incubator chambers (Modular Incubator Chambers MIC-101,…
7	Methods — Phagocytosis assay	Phagocytosis was assessed in rat primary microglial cells. For this, the cell culture media was…
8	Methods — Nitrite production	Inflammatory activation of microglia was assessed indirectly as the production of nitrites in the…
9	Methods — RNA isolation	RNA was isolated using Direct-zol RNA MicroPrep (Zymo Research, Irvine, CA, USA) according to…
10	Methods — Library generation	Illumina compatible libraries were prepared from RNA using QuantSeq 3′ mRNA-seq Library Prep Kit…
11	Methods — RNA sequencing and analysis	Barcoded libraries were pooled and sequenced on Illumina NextSeq system (Illumina, San Diego, CA,…
12	Methods — Quantitative real-time PCR	Whole cell RNA (1 μg) was converted to cDNA using the High Capacity cDNA Reverse Transcription Kit…
13	Methods — Data analysis	Data are presented as mean ± SEM of at least three independent experiments. qPCR data were compared…
14	Results — Alcohol increases microglial inflammatory activation	Enriched (> 95%) primary microglia were prepared by the shake-off method from postnatal day 2 rat…
15	Results — Alcohol-dependent changes in microglial mRNA	RNAseq analysis was used to identify mRNAs regulated by exposure to alcohol. Of 17,327 genes in the…
16	Results — Alcohol-dependent changes in microglial mRNA	To compare microglial responses to alcohol to those elicited by an inflammatory stimulus, we carried…
17	Results — Alcohol-dependent changes in microglial mRNA	Comparison (Fig. 3 and Additional file 1: Table S4) of Alc-DEs (regions 1, 2, 4, and 5) to TII-DEs…
18	Results — Alcohol-dependent changes in microglial mRNA	Gene Ontology analysis (DAVID) identified five KEGG pathways enriched in the 312 Alc-DE group…
19	Results — Alcohol-dependent changes in microglial mRNA	as an enriched cytosolic component. However, this group includes all 3 isoforms of complement…

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Title	Year	PMID
Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism.	2019	30765688

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Gene-environment interactions in Alzheimer's disease: A potential path to precision medicine.	Eid A et al.	—	2019	→