Acute IL-6 exposure triggers canonical IL-6R signalling in hiPSC microglia, but not neural progenitor cells.

Couch, A. C. M.; Solomon, S.; Marrocu, A.; Duarte, R.; Sun, Y.; Sichlinger, L.; Matuleviciute, R.; Dutan Polit, L.; Hanger, B.; Kordasti, S.; Srivastava, D. P.; Vernon, A. C.

doi:10.1101/2022.08.05.502958

bioRxiv · 10.1101/2022.08.05.502958

Acute IL-6 exposure triggers canonical IL-6R signalling in hiPSC microglia, but not neural progenitor cells.

Couch, A. C. M.·Solomon, S.·Marrocu, A.·Duarte, R.·Sun, Y.·Sichlinger, L.·Matuleviciute, R.·Dutan Polit, L.·Hanger, B.·Kordasti, S.·Srivastava, D. P.·Vernon, A. C.

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Abstract

BackgroundExposure to elevated interleukin (IL)-6 levels in utero is consistently associated with increased risk for psychiatric disorders with a putative neurodevelopmental origin, such as schizophrenia (SZ) and autism spectrum condition (ASC). 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 characterised the response of hiPSC-derived microglia-like cells (MGL) and neural progenitor cells (NPCs) to IL-6 in monoculture. ResultsWe observed that human forebrain NPCs did not respond to acute IL-6 exposure in monoculture at both a protein and transcript level due to the absence of IL-6Ra expression and sIL-6Ra secretion. By contrast, acute IL-6 exposure resulted in STAT3 phosphorylation and increased IL-6, JMJD3 and IL-10 expression in MGL, confirming activation of canonical IL-6R signalling. Bulk RNAseq identified 156 upregulated genes (FDR <0.05) in MGL following acute IL-6 exposure, including IRF8, REL, HSPA1A/B and OXTR, which significantly overlapped with an upregulated gene set from post-mortem brain tissue from individuals with schizophrenia. Acute IL-6 stimulation significantly increased MGL motility suggestive of a gain of surveillance function, consistent with gene ontology pathways highlighted from the RNAseq data. Finally, MGLs displayed elevated CCL1, CXCL1, MIP-1A/B, IL-8, IL-13, IL-16, IL-18, MIF and Serpin-E1 secretion post 3h and 24h IL-6 exposure. ConclusionOur data provide evidence for cell specific effects of acute IL-6 exposure in a human model system and strongly suggest 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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Couch, A. C. M., Solomon, S., Marrocu, A., Duarte, R., Sun, Y., Sichlinger, L., Matuleviciute, R., Dutan Polit, L., Hanger, B., Kordasti, S., Srivastava, D. P., Vernon, A. C.. 2022-08-06. Acute IL-6 exposure triggers canonical IL-6R signalling in hiPSC microglia, but not neural progenitor cells.. https://doi.org/10.1101/2022.08.05.502958

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