Background  The dysfunction of dendritic cell (DC) is one of the major causes for the pathogenesis and development of sepsis. Lactic acid, an essential mesostate of anaerobic glycolysis, reveals obviously inhibitory effects on multiple immune cells, including DCs.

  Objective  To investigate the effects of hyperlacticaemia on the function of DC in sepsis and related mechanism.

  Methods  C57BL/6 mice were randomly divided into sham group and sepsis group. The septic mice model was established by cecal ligation and puncture. Blood gas analyzer was used to measure the concentration of serum lactic acid. The spleen DCs were isolated by anti-mouse CD11c⁺ immune microbeads, and the expressions of DC surface molecules, including CD80, CD86 and MHC-Ⅱ, were detected by flow cytometry. The enzyme-linked immunosorbent assay (ELISA) was applied to assess the expressions of multiple cytokines, such as IL-2, IL-4, IL-12 and IFN-γ, and the formation and number of autophagosomes were observed by laser confocal microscope.

  Results  The concentration of blood lactic acid increased significantly in septic mice when compared with that in the sham group, which was noteworthy at 24 h and 48 h after operation (24 h: 2.61 ± 0.54 mmol/L vs 1.43 ± 0.58 mmol/L, P＜0.01; 48 h: 2.12 ± 0.51 mmol/L vs 1.32 ± 0.53 mmol/L, P＜0.01; DC in septic mice showed significantly elevated expressions of surface molecules, including CD80, CD86 and MHC-Ⅱ (CD80: 61.40% ± 9.20% vs 7.94% ± 1.01%, P＜0.05; MHC-Ⅱ: 79.91% ± 8.32% vs 30.34% ± 2.47%, P＜0.05), which was capable of priming T cell response by promoting secretion of IFN-γ and polarization of Th1 subtypes. While the function of DC was significantly inhibited at 48 h after sepsis exposure, which further induced Th2 cell polarization (IFN-γ/IL4: 0.41 ± 0.06 vs 1.00 ± 0.00, P＜0.01); The function of DC was significantly suppressed in response to in-vitro lactic acid stimuli which caused remarkable downregulation in the expression of surface molecules and failed priming T cell response (LPS group vs Lactic acid group: CD80: 5.11% ± 0.52% vs 0.09% ± 0.02%, P < 0.01; MHC-Ⅱ: 96.89% ± 0.16% vs 95.96% ± 0.20%, P＜0.05; CD86: 67.26% ± 1.23% vs 32.45% ± 2.95%, P＜0.01; IL2: 3.12 ± 1.25 pg/mL vs 0.44 ± 0.14 pg/mL, P＜0.05). The same tendency was noted with combined stimuli between LPS and lactic acid in DC, but no significant difference was found when compared with those in the lactic acid group (P＞0.05); Over-activation of autophagy was noted in DC under exposure to both sepsis and lactic acid, and the inhibited effects of lactic acid on DC function were reversed by administration of 3-MA and Bafilomycin.

  Conclusion  Hyperlacticaemia may be an essential reason for dysfunction of DCs under septic exposure. Over-activation of autophagy is involved in the dysfunction of DCs by lactic acid stimuli, and the combined regulation between autophagic activity and lactic acid level may be an effective remedy to improve sepsis-induced dysfunction of DC.