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| Status |
Public on Sep 30, 2024 |
| Title |
Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background: Prenatal exposure to elevated interleukin (IL)-6 levels is associated with increased risk for psychiatric disorders with a putative neurodevelopmental origin, such as schizophrenia (SZ), autism spectrum condition (ASC) and bipolar disorder (BD). Although rodent models provide causal evidence for this association, we lack a detailed understanding of the cellular and molecular mechanisms in human model systems. To close this gap, we characterized the response of human induced pluripotent stem cell (hiPSC-)derived microglia-like cells (MGL) and neural progenitor cells (NPCs) to IL-6 in monoculture.
Results: We observed that human forebrain NPCs did not respond to acute IL-6 exposure in monoculture at both protein and transcript levels due to the absence of IL6R expression and soluble (s)IL6Ra secretion. By contrast, acute IL-6 exposure resulted in STAT3 phosphorylation and increased IL6, JMJD3 and IL10 expression in MGL, confirming activation of canonical IL6Ra signaling. Bulk RNAseq identified 156 up-regulated genes (FDR < 0.05) in MGL following acute IL-6 exposure, including IRF8, REL, HSPA1A/B and OXTR, which significantly overlapped with an up-regulated gene set from human post-mortem brain tissue from individuals with schizophrenia. Acute IL-6 stimulation significantly increased MGL motility, consistent with gene ontology pathways highlighted from the RNAseq data and replicating rodent model indications that IRF8 regulates microglial motility. Finally, IL-6 induces MGLs to secrete CCL1, CXCL1, MIP-1α/β, IL-8, IL-13, IL-16, IL-18, MIF and Serpin-E1 after 3h and 24h.
Conclusion: Our data provide evidence for cell specific effects of acute IL-6 exposure in a human model system, ultimately suggesting that microglia-NPC co-culture models are required to study how IL-6 influences human cortical neural progenitor cell development in vitro.
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| Overall design |
To characterize the response of human induced pluripotent stem cell (hiPSC-)derived microglia-like cells (MGL) in monoculture, we exposed N=3 donor lines (M3_CTR_36S, 127_CTM_01 and 014_CTM_02) on day 14 of MGL differentiation to 3h of IL-6 stimulation (100ng/ml) and carried out bulk-RNAseq analysis to profile the MGL's transcriptomic response.
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| Contributor(s) |
Couch A, Vernon AC |
| Citation(s) |
36781081 |
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| Submission date |
Sep 27, 2024 |
| Last update date |
Sep 30, 2024 |
| Contact name |
Amalie Charlotte Maria Couch |
| E-mail(s) |
amaliecouch@gmail.com
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| Organization name |
King's College London
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| Department |
Basic and Clinical Neuroscience
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| Lab |
Vernon Lab
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| Street address |
5 Cutcombe Road
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| City |
London |
| ZIP/Postal code |
SE5 9RX |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA1166124 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE278224_raw_counts.txt.gz |
864.4 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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