Tissue-specific inflammatory responses to systemic LPS in mice with LysM-lineage Hmgb1 deletion

Systemic lipopolysaccharide (LPS) exposure induces peripheral inflammation that can engage neuroimmune pathways. High-mobility group box 1 (HMGB1) may contribute to peripheral-central communication, but the role of lysozyme M (LysM)-expressing cells in circulating HMGB1 and compartment-specific inflammatory responses remains unclear.

Male 7-8-week-old HMGB1 ^fl/fl LysM-Cre ⁺  mice and HMGB1 ^fl/fl LysM-Cre ^- littermate controls received LPS (5 mg/kg, i.p.) or saline. Plasma HMGB1, midbrain inflammatory gene expression, cervical lymph node (CLN) transcriptional responses, and choroid plexus CD45 immunoreactivity were assessed at 3 h and 7 days. Spleen, liver, and bone marrow transcriptional responses and Y-maze performance were assessed at 7 days.

LPS increased plasma HMGB1 at 3 h and 7 days without significant genotype differences. Despite comparable circulating HMGB1, LysM-lineage Hmgb1 deletion was associated with altered expression of selected midbrain inflammatory transcripts at both time points and with distinct acute and temporal CLN transcriptional responses. At 7 days, splenic responses largely overlapped between genotypes, whereas liver and bone marrow gene-level responses were limited. LPS increased choroid plexus CD45 immunoreactivity at both time points without genotype effects. Y-maze outcomes showed no significant genotype, treatment, or interaction effects.

LysM-lineage Hmgb1 deletion is associated with compartment- and time-dependent inflammatory responses following sublethal LPS-induced endotoxemia. The dissociation between plasma HMGB1 and genotype-associated midbrain and CLN responses indicates that total circulating HMGB1 did not fully reflect compartment-specific responses in this model, highlighting the importance of anatomical context in peripheral-central immune signaling.