Background Tolerogenic dendritic cells (DCs) are associated with poor prognosis of sepsis. Matrix metalloproteinases (MMPs) have been shown to have immunomodulatory effects. However, whether MMPs are involved in the functional reprogramming of DCs is unknown. The study aims to investigate the role of MMPs in sepsis-induced DCs tolerance and the potential mechanisms. Methods A murine model of late sepsis was induced by cecal ligation and puncture (CLP). The expression levels of members of the MMP family were detected in sepsis-induced tolerogenic DCs by using microarray assessment. The potential roles and mechanisms underlying MMP8 in the differentiation, maturation and functional reprogramming of DCs during late sepsis were assessed both in vitro and in vivo. Results DCs from late septic mice expressed higher levels of MMP8, MMP9, MMP14, MMP19, MMP25 and MMP27, and MMP8 levels were the highest. MMP8 deficiency significantly alleviated sepsis-induced immune tolerance of DCs both in vivo and in vitro. Adoptive transfer of MMP8 knockdown post-septic bone marrow-derived DCs protected mice against sepsis-associated lethality and organ dysfunction, inhibited regulatory T-cell expansion and enhanced Th1 response. Furthermore, the effect of MMP8 on DC tolerance was found to be associated with the nuclear factor kappa-B p65/β-catenin pathway. Conclusions Increased MMP8 levels in septic DCs might serve as a negative feedback loop, thereby suppressing the proinflammatory response and inducing DC tolerance.

中文翻译：

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基质金属蛋白酶-8 通过核因子 kappa-B p65/β-catenin 通路调节晚期多微生物脓毒症中的树突状细胞耐受性


背景 耐受性树突状细胞（DC）与脓毒症的不良预后相关。基质金属蛋白酶（MMP）已被证明具有免疫调节作用。然而，MMP 是否参与 DC 的功能重编程尚不清楚。本研究旨在探讨MMPs在脓毒症诱导的DCs耐受中的作用及其潜在机制。方法采用盲肠结扎穿刺法（CLP）诱导小鼠晚期脓毒症模型。通过使用微阵列评估，检测脓毒症诱导的耐受性 DC 中 MMP 家族成员的表达水平。在体外和体内评估了 MMP8 在脓毒症晚期 DC 分化、成熟和功能重编程中的潜在作用和机制。结果脓毒症晚期小鼠DCs表达较高水平的MMP8、MMP9、MMP14、MMP19、MMP25和MMP27，其中MMP8水平最高。 MMP8 缺陷在体内和体外均显着减轻脓毒症诱导的 DC 免疫耐受。 MMP8 敲低脓毒症后骨髓来源的 DC 的过继转移可以保护小鼠免受脓毒症相关的致死和器官功能障碍，抑制调节性 T 细胞扩增并增强 Th1 反应。此外，发现 MMP8 对 DC 耐受性的影响与核因子 kappa-B p65/β-catenin 通路有关。结论 脓毒症 DC 中 MMP8 水平升高可能作为负反馈回路，从而抑制促炎反应并诱导 DC 耐受。