Interferon-γ exposure of human iPSC-derived neurons alters major histocompatibility complex I and synapsin protein expression

Abstract

Human epidemiological data links maternal immune activation (MIA) during gestation with increased risk for psychiatric disorders with a putative neurodevelopmental origin, including schizophrenia and autism. Animal models of MIA provide evidence for this association and suggest that inflammatory cytokines represent one critical link between maternal infection and any potential impact on offspring brain and behavior development. However, to what extent specific cytokines are necessary and sufficient for these effects remains unclear. It is also unclear how specific cytokines may impact the development of specific cell types. Using a human cellular model, we recently demonstrated that acute exposure to interferon-γ (IFNγ) recapitulates molecular and cellular phenotypes associated with neurodevelopmental disorders. Here, we extend this work to test whether IFNγ can impact the development of immature glutamatergic neurons using an induced neuronal cellular system. We find that acute exposure to IFNγ activates a signal transducer and activator of transcription 1 (STAT1)-pathway in immature neurons, and results in significantly increased major histocompatibility complex I (MHCI) expression at the mRNA and protein level. Furthermore, acute IFNγ exposure decreased synapsin I/II protein in neurons but did not affect the expression of synaptic genes. Interestingly, complement component 4A (C4A) gene expression was significantly increased following acute IFNγ exposure. This study builds on our previous work by showing that IFNγ-mediated disruption of relevant synaptic proteins can occur at early stages of neuronal development, potentially contributing to neurodevelopmental disorder phenotypes.

Immunogenicity of autologous and allogeneic human primary cholangiocyte organoids

“…Our data demonstrate that PCOs, similar to primary cholangiocytes, upregulate both HLA-I (A, B and C) and HLA-II (DP, DQ and DR) in inflammatory conditions in vitro and in vivo . Consistent with our findings, upregulation of HLA in inflammatory in vitro conditions has been previously reported for other putative cellular therapies derived from iPS or ES cells ( 36 – 39 ). The magnitude of the in vitro and in vivo immune responses (as measured by the total number of CD45+ infiltrating immune cells) to allogeneic PCOs was significantly reduced by donor-recipient matching at HLA-I but was nonetheless greater than autologous control PCOs, driven by mismatch at HLA-II.…”

“…Consistent with our findings, upregulation of HLA in inflammatory in vitro conditions has been previously reported for other putative cellular therapies derived from iPS or ES cells (36)(37)(38)(39).…”

Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons

“…We next studied ZNF804A isoform expression in developing glutamatergic cortical neurons by employing a forward programming approach (Pavlinek et al, 2022; Pawlowski et al, 2017). To avoid heterogeneity in the population of glutamatergic cell type generated by this approach (Treutlein et al, 2016), NGN2 overexpression was combined with a directed differentiation approach utilizing SMAD and Wnt inhibition (Nehme et al, 2018).…”

The human lncRNA GOMAFU suppresses neuronal interferon response pathways affected in neuropsychiatric diseases

“…S9E and F ). These include MT2A and TRIM5 , which are significantly increased in frontal cortex of SCZ along with reduced GOMAFU ( Gandal et al, 2018 ) and HLA-B/C known to be induced by IFN-γ in NPC and neurons derived from different paradigms ( Pavlinek et al, 2022 ; Warre-Cornish et al, 2020 ). These data are consistent with the hypothesis that GOMAFU downregulation may contribute to enhanced IFN-γ responses.…”