HLA DP/DRA molecule regulates systemic inflammation and neuroinflammation, aggravates cognitive impairment and long-term anxiety in murine model of sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a severe and common neurological complication of sepsis, characterized by symptoms ranging from mild confusion, delirium, deep coma, and severe cognitive dysfunction. Previous epidemiological and bioinformatics studies have revealed that HLA DP and DRA molecule play a pivotal role during sepsis. However, the mechanism by which these class II molecule contribute to cognitive impairment in SAE remains unclear. using the peritoneal contamination and infection model (PCI) model in humanized transgenic HLA-DP401/DRA-IAβ-/- genotypes mice, we aimed to investigate the effects of HLA class II haplotypes/alleles on sepsis and elucidate the underlying mechanism leading to cognitive impairment. Our results indicated that the introduction of HLA DP/DRA molecule significantly increased mortality, exacerbated clinical symptoms, and elevated inflammatory cytokine responses in both serum and hippocampal tissue of septic mice. Cecal slurry (CS) injection induced robust microglia activation and severe pathological damage of hippocampus. Furthermore, transcriptome analysis revealed numerous differentially expressed genes (DEGs) and prominent mitochondrial dysfunction in HLA-DP/DRA-IAβ-/- mice subjected to PCI. Notably, CS injection up-regulated AMPK-α phosphorylation in IAβ-/- mice but not in HLA DP/DRA-IAβ-/- mice. Consistently, sepsis induced persistent neurocognitive deficits and long-term anxiety-like behaviors in HLA DP/DRA-IAβ-/- PCI mice. In conclusion, these data provide direct evidence that HLA class II molecules modulate the host response to sepsis and highlight a critical role of HLA-DP/DRA in exacerbating the severity of systemic infection. The introduction of the HLA-DP and HLA-DRA genes synergistically upregulated systemic and hippocampal inflammatory cytokines, worsened clinical outcomes, impaired memory performance, and exacerbated long-term anxiety-like behaviors.