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Effects of cytokines on nuclear factor-kappa B, cell viability, and synaptic connectivity in a human neuronal cell line

Molecular Psychiatry volume 26, pages 875–887 (2021)Cite this article

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Abstract

Maternal infection during pregnancy is associated with increased risk of psychiatric and neurodevelopmental disorders (NDDs). Experimental animal models demonstrate that maternal immune activation (MIA) elevates inflammatory cytokine levels in the maternal and fetal compartments and causes behavioral changes in offspring. Individual cytokines have been shown to modulate neurite outgrowth and synaptic connectivity in cultured rodent neurons, but whether clinically relevant cytokine mixtures similarly modulate neurodevelopment in human neurons is not known. To address this, we quantified apoptosis, neurite outgrowth, and synapse number in the LUHMES human neuronal cell line exposed to varying concentrations of: (1) a mixture of 12 cytokines and chemokines (EMA) elevated in mid-gestational serum samples from mothers of children with autism and intellectual disability; (2) an inflammatory cytokine mixture (ICM) comprised of five cytokines elevated in experimental MIA models; or (3) individual cytokines in ICM. At concentrations that activated nuclear factor-kappa B (NF-κB) in LUHMES cells, EMA and ICM induced caspase-3/7 activity. ICM altered neurite outgrowth, but only at concentrations that also reduced cell viability, whereas ICM reduced synapse number independent of changes in cell viability. Individual cytokines in ICM phenocopied the effects of ICM on NF-κB activation and synaptic connectivity, but did not completely mimic the effects of ICM on apoptosis. These results demonstrate that clinically relevant cytokine mixtures modulate apoptosis and synaptic density in developing human neurons. Given the relevance of these neurodevelopmental processes in NDDs, our findings support the hypothesis that cytokines contribute to the adverse effects of MIA on children.

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Fig. 1: ICM exposure causes concentration-dependent NF-κB p65 activation in LUHMES cells.
Fig. 2: ICM selectively alters cytokine receptor expression in LUHMES cells.
Fig. 3: ICM decreases neurite outgrowth and increases apoptosis on D3.
Fig. 4: ICM decreases neurite outgrowth and increases apoptosis on D6.
Fig. 5: ICM decreases synaptic puncta.

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Data availability

The data sets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This research was supported by the National Institute of Environmental Health Sciences (grants P01 ES011269 and P30 ES023513) and the United States Environmental Protection Agency (grant R83543201). This research used the Biological Analysis Core of the UC Davis MIND Institute Intellectual and Developmental Disabilities Research Center (U54 HD079125).

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  1. These authors contributed equally: Judy Van de Water, Pamela J. Lein

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  1. Department of Internal Medicine, University of California, Davis, CA, USA

    Lauren Matelski & Judy Van de Water

  2. Department of Molecular Biosciences, University of California, Davis, CA, USA

    Lauren Matelski, Rhianna K. Morgan, Ana Cristina Grodzki & Pamela J. Lein

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Matelski, L., Morgan, R.K., Grodzki, A.C. et al. Effects of cytokines on nuclear factor-kappa B, cell viability, and synaptic connectivity in a human neuronal cell line. Mol Psychiatry 26, 875–887 (2021). https://doi.org/10.1038/s41380-020-0647-2

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