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

SUMMARY

“Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis” investigates how specific Th17 effector cytokines—particularly IL-17A and GM-CSF—contribute to damaging the Blood Brain Barrier (BBB) and causing brain inflammation following multiple Group A Streptococcus (GAS) infections.

Using a mouse model and multi-modal analysis including single-cell RNA sequencing, MERFISH spatial transcriptomics, and cytokine profiling, researchers identified that endothelial cells (ECs) downregulate BBB-related genes and microglia upregulate inflammatory, interferon-response, and antigen-presentation genes after multiple Group A strep infections.

Importantly, neutralization of IL-17A, but not deletion of GM-CSF in T cells, significantly rescued Blood Brain Barrier integrity and dampened microglial pro-inflammatory signaling.

Additionally, key inflammatory markers found in murine models were also elevated in the serum of children with PANDAS/PANS, indicating a shared inflammatory signature. These findings provide molecular evidence that IL-17A plays a pivotal role in driving CNS pathology in this model and suggest that targeting IL-17A could be a potential treatment option for children who don’t respond to current therapies.

LINK TO PAPER: https://doi.org/10.1101/2023.03.10.532135