Introduction: Severe traumatic brain injury (TBI) is a leading cause of pediatric disability and mortality. Current care is largely supportive, with no therapies shown to improve outcomes. We hypothesized that differential gene expression patterns would reveal pathways with potential therapeutic implications in severe TBI. Methods: After IRB approval (CWH 2021-096) and informed consent, seventeen pediatric severe TBI patients ages ≥ 1 and ≤ 21 years were prospectively enrolled. Serial blood samples were collected at 24 ± 12 hours (timepoint 1), 48 ± 12 hours (timepoint 2), and on hospital day 9 ± 12 (timepoint 3) hours. Demographics and clinical variables were extracted from the medical record. Blood samples from ten control patients were obtained at a single timepoint. RNA expression was extrapolated using matching reads to human genes using Salmon quasi-alignments with STRING based gene ontology enrichment; and assessed for immune repertoire using MiXCR and ImmuneArch. Results: Severe TBI patients revealed sequential transcriptomic changes over time, with Principal Component Analysis (PCA) showing clustering of transcripts from timepoints 1 and 2, and unique clustering of transcripts in timepoint 3. Bulk transcriptomics data revealed inflammatory and immune-mediated gene expression pathways, including those associated with leukocyte and T cell infiltration, macrophage activation, and neutrophil-related aggregation and degranulation. Early timepoints showed increased gene expression of the S100 family, including the S100A8/A9 complex. Conclusions: S100A8/A9, or calprotectin, is an alarmin secreted by activated neutrophils, and is increasingly being recognized as a critical mediator of inflammation in a number of systemic diseases. It has recently been shown to play a critical pathologic role in TBI-related neuroinflammation in pre-clinical murine models, and may serve as a mechanistic link between TBI and chronic neurodegenerative diseases. This is the first study to our knowledge documenting gene expression changes related to S100A8/A9 in pediatric TBI. Its specific contribution to pediatric TBI-related neuroinflammation, and its role in chronic pediatric neuropathology remains largely unexplored, and may serve as a promising therapeutic target.
Hussain et al. (Sun,) studied this question.