Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis

Wayne, C. R.; Bremner, L. I.; Faust, T. E.; Duran-Laforet, V.; Ampatey, N.; Ho, S. J.; Feinberg, P. A.; Arvanitis, P.; Ciric, B.; Delaney, S. L.; Vargas-Deming, W.; Swedo, S.; Menon, V.; Schafer, D. P.; Cutforth, T.; Agalliu, D.

doi:10.1101/2023.03.10.532135

bioRxiv · 10.1101/2023.03.10.532135

Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis

Wayne, C. R.·Bremner, L. I.·Faust, T. E.·Duran-Laforet, V.·Ampatey, N.·Ho, S. J.·Feinberg, P. A.·Arvanitis, P.·Ciric, B.·Delaney, S. L.·Vargas-Deming, W.·Swedo, S.·Menon, V.·Schafer, D. P.·Cutforth, T.·Agalliu, D.

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Abstract

Group A Streptococcus (GAS) infections can cause neuropsychiatric sequelae in children due to post-infectious encephalitis. Multiple GAS infections induce migration of Th17 lymphocytes from the nose into the brain, which are critical for microglial activation, blood-brain barrier (BBB) and neural circuit impairment in a mouse disease model. How endothelial cells (ECs) and microglia respond to GAS infections, and which Th17-derived cytokines are essential for these responses are unknown. Using single-cell RNA sequencing and spatial transcriptomics, we found that ECs downregulate BBB genes and microglia upregulate interferon-response, chemokine and antigen-presentation genes after GAS infections. Several microglial-derived chemokines were elevated in patient sera. Administration of a neutralizing antibody against interleukin-17A (IL-17A), but not ablation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, partially rescued BBB dysfunction and microglial expression of chemokine genes. Thus, IL-17A is critical for neuropsychiatric sequelae of GAS infections and may be targeted to treat these disorders.

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Wayne, C. R., Bremner, L. I., Faust, T. E., Duran-Laforet, V., Ampatey, N., Ho, S. J., Feinberg, P. A., Arvanitis, P., Ciric, B., Delaney, S. L., Vargas-Deming, W., Swedo, S., Menon, V., Schafer, D. P., Cutforth, T., Agalliu, D.. 2023-03-12. Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis. https://doi.org/10.1101/2023.03.10.532135

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