Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
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 3 h and 24 h.
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:110 |
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| Enthalten in: |
Brain, behavior, and immunity - 110(2023) vom: 23. Mai, Seite 43-59 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Couch, Amalie C M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.04.2023 Date Revised 13.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bbi.2023.02.007 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Couch, Amalie C M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Revised 13.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 3 h and 24 h | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Human induced-pluripotent stem cells | |
| 650 | 4 | |a IL-6 | |
| 650 | 4 | |a Microglia | |
| 650 | 4 | |a Neural progenitor cells | |
| 650 | 4 | |a Neurodevelopmental disorders | |
| 650 | 7 | |a Interferon Regulatory Factors |2 NLM | |
| 650 | 7 | |a Interleukin-6 |2 NLM | |
| 650 | 7 | |a Receptors, Interleukin-6 |2 NLM | |
| 700 | 1 | |a Solomon, Shiden |e verfasserin |4 aut | |
| 700 | 1 | |a Duarte, Rodrigo R R |e verfasserin |4 aut | |
| 700 | 1 | |a Marrocu, Alessia |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Yiqing |e verfasserin |4 aut | |
| 700 | 1 | |a Sichlinger, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Matuleviciute, Rugile |e verfasserin |4 aut | |
| 700 | 1 | |a Polit, Lucia Dutan |e verfasserin |4 aut | |
| 700 | 1 | |a Hanger, Bjørn |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Amelia |e verfasserin |4 aut | |
| 700 | 1 | |a Kordasti, Shahram |e verfasserin |4 aut | |
| 700 | 1 | |a Srivastava, Deepak P |e verfasserin |4 aut | |
| 700 | 1 | |a Vernon, Anthony C |e verfasserin |4 aut | |
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