Molecular and spatial heterogeneity of microglia in Rasmussen encephalitis

• DOI: 10.1186/s40478-022-01472-y
• Publication Date: 2022-11-21T10:03:04Z
• Authors: Jesse J. Westfall; Wesley N. Schwind; Sahibjot Sran; Jason B. Navarro; Jeffrey Leonard; Jonathan A. Pindrik; Christopher R. Pi...; Daniel R. Boué; Daniel C. Koboldt; Adam P. Ostendorf; Richard K. Wilson; Elaine R. Mardis; Katherine E. Miller; Tracy A. Bedrosian
• Keywords: Proteomics; Inflammation; 0301 basic medicine; Epilepsy; Spatial proteomics; Research; 3. Good health; 03 medical and health sciences; Microglial nodules; Humans; Encephalitis; Neurology. Diseases of the nervous system; Microglia; RC346-429; Child; Single nucleus RNA-seq

Abstract Rasmussen encephalitis (RE) is a rare childhood neurological disease characterized by progressive unilateral loss of function, hemispheric atrophy and drug-resistant epilepsy. Affected brain tissue shows signs infiltrating cytotoxic T-cells, microglial activation, neuronal death, implicating an inflammatory process. Recent studies have identified molecular correlates inflammation in RE, but cell-type-specific mechanisms remain unclear. We used single-nucleus RNA-sequencing (snRNA-seq) to assess gene expression across multiple cell types resected from two children with RE. found transcriptionally distinct populations enriched RE compared age-matched individuals unaffected Type I focal cortical dysplasia (FCD). Specifically, microglia tissues demonstrated increased genes associated cytokine signaling, interferon-mediated pathways, T-cell activation. extended these findings using spatial proteomic analysis four surgical resections examine profiles within their pathological context. Microglia that were spatially aggregated into nodules had dynamic immune regulatory markers (PD-L1, CD14, CD11c), activation (CD40, CD80) physically located near CD4+ CD8+ lymphocyte populations. These help elucidate the complex microenvironment