A conserved monocyte activation program links brain injury to systemic immune adaptation and clinical outcomes.

Rationale: Systemic immune dysregulation after traumatic brain injury (TBI) contributes to secondary complications and influences long-term recovery, yet the cellular and molecular dynamics remain incompletely understood. Objectives: To characterize longitudinal immune responses following TBI and identify conserved transcriptional programs linked to clinical outcomes and mechanistically regulated monocyte states with potential prognostic and therapeutic significance. Methods: We conducted longitudinal transcriptomic profiling of PBMCs from TBI patients (n =65 samples) at Day 1, Day 7, and Month 6 post-injury, alongside healthy controls (n =24). Cell type composition was assessed using computational deconvolution and validated by flow cytometry. Gene co-expression networks were constructed to identify temporally dynamic immune signatures. Monocyte-specific metabolic activity was inferred using genome-scale metabolic modeling and confirmed by plasma metabolite quantification. Genome-wide chromatin state was assessed by H3K27ac ChIP-sequencing in CD14 Main results: TBI patients showed a transient increase in circulating monocytes at Day 1 and Day 7, returning to baseline by Month 6. Weighted gene co-expression analysis identified a data-driven monocyte-associated co-expression module (Yellow module) that dominated early responses and tracked with monocyte abundance. This module was conserved in sorted CD14 Conclusions: TBI induces a prognostically informative, monocyte-enriched transcriptional program marked by inflammatory and metabolic reprogramming. This epigenetically regulated state is conserved across critical illness, correlates with patient outcomes, and identifies PU.1 as a key regulator of monocyte activation. These findings support the Yellow module as a candidate biomarker for risk stratification and a mechanistic link between brain injury and systemic immune adaptation.