Multi‐Organ Inflammatory and Endocrine Crosstalk Shapes the Early Brain Response to Combined Burn and Blast Injury

The pathology of concomitant burn and traumatic brain injury remains poorly defined, despite their frequent co-occurrence in military settings and the potential for deleterious synergy. To address this gap, we combined established models of blast-induced mild traumatic brain injury and 15% total body surface area flame burn to approximate a common combat-related trauma and examined how the injuries interact to shape systemic inflammation and brain transcriptional programs. Burn injury induced systemic G-CSF and IL-6 secretion and hematopoietic reprioritization, whereas overlapping brain injury did not substantially alter these systemic effects but magnified brain transcriptional responses relative to single injuries. Bulk RNA-seq profiling at 6 h post-injury revealed enriched gene sets associated with inflammation and endocrine stress in the combined injury group, alongside elevated systemic cytokines and corticosterone; thereby suggesting concurrent immune-endocrine activation. Since our prior work demonstrated burn wound-associated IL-1 signaling induces G-CSF and IL-6 secretion, we tested IL-1 neutralizing antibodies and anakinra as therapies. Treatment reduced G-CSF and IL-6 secretion, improved erythropoiesis, and selectively modulated brain transcriptional changes. Single-nucleus RNA-seq projection mapping predicted that the transcripts altered by combined injury were broadly enriched across vascular and glial cell types. Targeted expression profiling identified a shared brain-liver signature characterized by an IL-1/6-dependent inflammatory response alongside an interleukin-independent stress response. These findings highlight IL-1-responsive inflammatory signals and endocrine stress interactions within a multi-organ network that shapes the early brain transcriptional response to the combined injury.