World journal of gastroenterology · 2025
Sphinganine inhibits macrophage polarization and protects against sepsis-induced intestinal injury.
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Chen Yi-Fan, Wang Ze-Tian, Zhao Jian, Tang Jian-Guo, Zhang Bai-Yin
Аннотация
BACKGROUND: Sepsis-induced intestinal injury disrupts barrier function and exacerbates systemic inflammation, contributing to high mortality.
AIM: To investigate the mechanism by which sphinganine protects against sepsis-induced intestinal injury, focusing on macrophage polarization and toll like receptor 2 (TLR2)/nuclear factor kappa-B (NF-κB) signaling.
METHODS: A cecal ligation and puncture sepsis model was established in mice (n = 20/group). Treatments included sphinganine (15 mg/kg) and a TLR2 agonist [fibroblast-stimulating lipopeptide-1 (FSL-1), 10 μg/kg]. Serum markers [diamine oxidase (DAO), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6] were measured by enzyme-linked immunosorbent assay. Intestinal injury and macrophage polarization [cluster of differentiation (CD) 86+ M1, CD206+ M2] were assessed via hematoxylin and eosin and immunofluorescence staining. Proteomic analysis, molecular docking, and Western blot were used to evaluate TLR2/NF-κB signaling. Data were analyzed by analysis of variance and t-test.
RESULTS: Sphinganine significantly reduced serum levels of DAO (P < 0.05), IL-1β, TNF-α, and IL-6 (P < 0.05), preserved intestinal crypt structure, and enhanced tight junction protein zonula occludens-1 expression. It promoted a shift from M1 (CD86+) to M2 (CD206+) macrophages. Proteomics identified TLR2 as the most differentially expressed protein, and molecular docking confirmed strong binding between sphinganine and TLR2 (-4.3 kcal/mol). Sphinganine downregulated TLR2 and phosphorylated-NF-κB p65 expression (P < 0.05), effects reversed by FSL-1. Total NF-κB p65 levels remained unchanged.
CONCLUSION: Sphinganine protects against sepsis-induced intestinal injury by inhibiting TLR2/NF-κB signaling, modulating macrophage polarization toward the M2 phenotype, and preserving intestinal barrier integrity.
AIM: To investigate the mechanism by which sphinganine protects against sepsis-induced intestinal injury, focusing on macrophage polarization and toll like receptor 2 (TLR2)/nuclear factor kappa-B (NF-κB) signaling.
METHODS: A cecal ligation and puncture sepsis model was established in mice (n = 20/group). Treatments included sphinganine (15 mg/kg) and a TLR2 agonist [fibroblast-stimulating lipopeptide-1 (FSL-1), 10 μg/kg]. Serum markers [diamine oxidase (DAO), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6] were measured by enzyme-linked immunosorbent assay. Intestinal injury and macrophage polarization [cluster of differentiation (CD) 86+ M1, CD206+ M2] were assessed via hematoxylin and eosin and immunofluorescence staining. Proteomic analysis, molecular docking, and Western blot were used to evaluate TLR2/NF-κB signaling. Data were analyzed by analysis of variance and t-test.
RESULTS: Sphinganine significantly reduced serum levels of DAO (P < 0.05), IL-1β, TNF-α, and IL-6 (P < 0.05), preserved intestinal crypt structure, and enhanced tight junction protein zonula occludens-1 expression. It promoted a shift from M1 (CD86+) to M2 (CD206+) macrophages. Proteomics identified TLR2 as the most differentially expressed protein, and molecular docking confirmed strong binding between sphinganine and TLR2 (-4.3 kcal/mol). Sphinganine downregulated TLR2 and phosphorylated-NF-κB p65 expression (P < 0.05), effects reversed by FSL-1. Total NF-κB p65 levels remained unchanged.
CONCLUSION: Sphinganine protects against sepsis-induced intestinal injury by inhibiting TLR2/NF-κB signaling, modulating macrophage polarization toward the M2 phenotype, and preserving intestinal barrier integrity.