Circulating Toll-like receptor and cytokine profiles and genetic polymorphisms in a Chinese sepsis cohort: potential links to neuroinflammation and blood-brain barrier dysfunction.

Background: Sepsis is characterised by a dysregulated host response to infection and remains a major cause of morbidity and mortality. Toll-like receptor (TLR)-mediated inflammatory signalling can amplify systemic cytokine release and has been implicated in sepsis-associated brain dysfunction through neuroinflammation and blood-brain barrier (BBB) impairment. This study examined circulating TLR/cytokine profiles and common genetic polymorphisms in key inflammatory genes in patients with sepsis. Methods: In this hospital-based case-control study, 480 adult patients with sepsis admitted to the intensive care unit and 840 age- and sex-matched healthy controls were enrolled. Serum levels of TLR2, TLR4, TLR9, IL-1β, IL-6, IL-8, IL-10, TNF-α and IFN-γ were quantified by enzyme-linked immunosorbent assay at the time of sepsis diagnosis. Genotypes of candidate polymorphisms in TLR and cytokine-related genes were determined using a classical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. Hardy-Weinberg equilibrium was evaluated in the control group. Associations between polymorphisms and sepsis susceptibility were assessed using multivariable logistic regression adjusted for age and sex, and p values were interpreted with consideration of multiple comparisons, including conservative Bonferroni correction in sensitivity analyses. Results: Compared with controls, patients with sepsis exhibited significantly higher serum levels of TLR2, TLR4, TLR9, IL-1β, IL-6, IL-8, IL-10 and TNF-α (all p < 0.05), whereas IFN-γ levels were not significantly different. Several polymorphisms were associated with increased sepsis risk, including TLR2 -196 to -174 del, TLR4 rs1927911, TLR9 rs352140, TLR9 rs574836, IL-1B +3954 C/T, IL-6 -174 G/C, IL-10 -1082 G/A, IL-10 -819 T/C, TNF-α -308 G/A and IFN-γ +874 A/T (all p < 0.05), and a subset of these associations remained statistically significant after conservative correction for multiple testing. Conclusion: Circulating up-regulation of the TLR-cytokine axis and susceptibility-associated polymorphisms in TLR and cytokine genes support a genetic-inflammatory framework for sepsis in this Chinese cohort, with potential relevance to pathways implicated in sepsis-related neuroinflammation and BBB dysfunction. Because central nervous system involvement and BBB integrity were not directly measured in this study, these links should be regarded as inferential. The present findings motivate further studies incorporating direct central nervous system and BBB endpoints and external validation cohorts, and may inform future biomarker-guided risk stratification strategies.