Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells

Journal article

BackgroundPrenatal 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.ResultsWe 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.ConclusionOur 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

Authors: Couch, ACM; Solomon, S; Duarte, RRR; Marrocu, A; Sun, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Brain, Behavior, and Immunity
• Volume: 110
• Pages: 43-59
• Publication date: 2023-02-11
• DOI: 10.1016/j.bbi.2023.02.007
• EISSN: 1090-2139
• ISSN: 0889-1591
• Language: English
• Keywords: Immunology; Progenitor cell; Inflammation; Signal transduction; Wnt signaling pathway; Cell biology; Neural stem cell; Stem cell; Biology; Microglia