Abstract
IntroductionGalectin-9 ameliorates various inflammatory conditions including autoimmune diseases by regulating T cell and macrophage/dendritic cell (DC) functions. However, the effect of galectin-9 on polymicrobial sepsis has not been assessed.MethodsWe induced polymicrobial sepsis by cecal ligation and puncture (CLP) in mice. The survival rate was compared between galectin-9- and PBS-treated CLP mice. An ELISA was used to compare the levels of various cytokines in the plasma and culture supernatants. Fluorescence-activated cell sorting analysis was further performed to compare the frequencies of subpopulations of spleen cells.ResultsGalectin-9 exhibited a protective effect in polymicrobial sepsis as demonstrated in galetin-9 transgenic mice and therapeutic galectin-9 administration. In contrast, such effect was not observed in nude mice, indicating the involvement of T cells in galectin-9-mediated survival prolongation. Galectin-9 decreased TNFα, IL-6, IL-10 and, high mobility group box 1 (HMGB1) and increased IL-15 and IL-17 plasma and spleen levels. Galectin-9 increased the frequencies of natural killer T (NKT) cells and PDCA-1+ CD11c+ macrophages (pDC-like macrophages) but did not change the frequency of CD4 or CD8 T cells, γδT cells or conventional DC. As expected, galectin-9 decreased the frequency of Tim-3+ CD4 T cells, most likely Th1 and Th17 cells. Intriguingly, many spleen NK1.1+ NKT cells and pDC-like macrophages expressed Tim-3. Galectin-9 increased the frequency of Tim-3-expressing NK1.1+ NKT cells and pDC-like macrophages. Galectin-9 further increased IL-17+ NK1.1+ NKT cells.ConclusionThese data suggest that galectin-9 exerts therapeutic effects on polymicrobial sepsis, possibly by expanding NKT cells and pDC-like macrophages and by modulating the production of early and late proinflammatory cytokines.
Highlights
Galectin-9 ameliorates various inflammatory conditions including autoimmune diseases by regulating T cell and macrophage/dendritic cell (DC) functions
To uncover the mechanism by which Gal-9 prolongs the survival of cecal ligation and puncture (CLP) mice, we assessed the levels of proinflammatory cytokines such as Tumor necrosis factor (TNF)-α and IL-1β in the Peritoneal fluids (PF) of WT and Gal-9 TG mice at 24 hours after CLP
We previously showed that the levels of TNF-α and IL-12 in PF were significantly suppressed in Gal-9 TG mice during early periods (1 to 6 hours) of LPS-induced peritoneal inflammation [24]
Summary
Galectin-9 ameliorates various inflammatory conditions including autoimmune diseases by regulating T cell and macrophage/dendritic cell (DC) functions. Two types of animal sepsis model have been established: the lipopolysaccharide(LPS)-induced inflammation, and the cecal ligation and puncture (CLP) model of microbial sepsis. LPS stimulates macrophages to release large amounts of TNFα and IL-1β that can precipitate tissue injury and lethal shock. High mobility group box 1 (HMGB1) is thought to be a late mediator of endotoxin lethality in mice, and HMGB1 is first detectable in the circulation 8 hours after the onset of sepsis disease, subsequently increasing to plateau levels from 16 to 32 hours [3]. Administration of HMGB1-specific neutralizing antibodies beginning 24 hours after the onset of sepsis induced by CLP was shown to lead to a dose-dependent rescue of mice from lethal sepsis [4,5,6]
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