Bacterial sepsis is a serious life-threatening condition caused by an excessive immune response to infection. B-1 cells differ from conventional B-2 cells by their distinct phenotype and function. A subset of B-1 cells expressing CD5, known as B-1a cells, exhibits innate immune activity. Here we report that B-1a cells play a beneficial role in sepsis by mitigating exaggerated inflammation through a novel mechanism. Using a mouse model of bacterial sepsis, we found that the numbers of B-1a cells in various anatomical locations were significantly decreased. Adoptive transfer of B-1a cells into septic mice significantly attenuated systemic inflammation and improved survival, whereas B-1a cell-deficient CD19-/- mice were more susceptible to infectious inflammation and mortality. We also demonstrated B-1a cells produced ample amounts of IL-10 which controlled excessive inflammation and the mice treated with IL-10-deficient B-1a cells were not protected against sepsis. Moreover, we identified a novel intracellular signaling molecule, cAMP-response element binding protein (CREB), which serves as a pivotal transcription factor for upregulating IL-10 production by B-1a cells in sepsis through its nuclear translocation and binding to putative responsive elements on IL-10 promoter. Thus, the benefit of B-1a cells in bacterial sepsis is mediated by CREB and the identification of CREB in B-1a cells reveals a potential avenue for treatment in bacterial sepsis.

译文

细菌性败血症是由于对感染的过度免疫反应而引起的严重威胁生命的疾病。B-1细胞与常规B-2细胞的区别在于其独特的表型和功能。表达CD5的B-1细胞的子集 (称为B-1a细胞) 表现出先天免疫活性。在这里,我们报告B-1a细胞通过一种新的机制减轻过度的炎症在败血症中发挥有益的作用。使用细菌败血症的小鼠模型,我们发现不同解剖位置的B-1a细胞数量显着减少。将B-1a细胞过继转移至脓毒症小鼠可显著减轻全身性炎症并改善存活率,而B-1a细胞缺陷型CD19-/-小鼠更容易感染感染性炎症和死亡率。我们还证明了B-1a细胞产生足够量的控制过度炎症的IL-10,并且用IL-10-deficient B-1a细胞处理的小鼠不能防止败血症。此外,我们鉴定了一种新的细胞内信号分子,cAMP反应元件结合蛋白 (CREB),它是脓毒症中B-1a细胞通过其核易位和与IL-10启动子上推定的反应元件结合而上调IL-10产生的关键转录因子。因此,细菌败血症中B-1a细胞的益处由CREB介导,并且B-1a细胞中CREB的鉴定揭示了治疗细菌败血症的潜在途径。

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