The immunological role of IRA B cells in the immunosuppressive phase of sepsis

脓毒症是临床医学中的一个主要问题，原因是对其发病机制的了解不完全，因此缺乏有效的治疗方案。尽管中性粒细胞/巨噬细胞在炎症过程中的作用以前已经被描述过，但协调病原体消除的机制仍然知之甚少。新近发现的炎性红髓(IRP)B细胞可能通过选择性地产生丰富的粒细胞/巨噬细胞集落刺激因子(GM-CSF)，为中性粒细胞/单核细胞的紧急产生起到把关作用。在提议的项目中，我将测试IRPS通过协调中性粒细胞/单核细胞的紧急产生来控制败血症自然过程的假设。在将IRPS的转录组与其他B细胞亚群进行比较后，我将用来自GM-CSF-/-和B细胞-/-小鼠的50：50骨髓细胞重组照射后的C57BL/6小鼠，产生一个混合嵌合体。接下来将测试IRPS在脓毒症(盲肠结扎/穿孔)模型中的作用。读数将包括存活率、细菌计数、血/脾中中性粒细胞/单核细胞计数、炎症介质表达和肺/肝病理。这些将在wt小鼠、wt骨髓重组小鼠和混合嵌合体±IRPS中进行评估。在WT小鼠中的初步数据表明，位于脾中的IRPS通过诱导髓外骨髓生成来控制脓毒症中的菌血症。综上所述，这些实验将阐明IRPS如何参与败血症。这些见解可能会导致新的败血症和感染的治疗策略。

Sepsis is a major problem in clinical medicine due to an incomplete understanding of its’ pathomechanisms and, therefore, a lack of effective treatment options. Although the role of neutrophils/macrophages during inflammation has been described before, mechanisms that orchestrate pathogen elimination are still poorly understood. A recently discovered inflammatory red pulp (iRP) B cell may act as a gatekeeper for the emergency generation of neutrophils/monocytes by selectively producing abundant granulocyte/macrophage-colony stimulating factor (GM-CSF). In the proposed project I will test the hypothesis that iRPs control the natural course of sepsis by orchestrating the emergency production of neutrophils/monocytes. After comparing the transcriptome of iRPs with other B cell subsets I will generate a mixed chimera by reconstituting irradiated C57Bl/6 mice with 50:50 bone marrow cells from GM-CSF-/- and B cell-/- mice. This will be followed by testing the role of iRPs in a model of sepsis (cecal ligation/puncture). The read-outs will include survival rates, bacterial counts, neutrophil/monocyte counts in blood/spleen, expression of inflammatory mediators and lung/liver pathology. These will be assessed in wt mice, mice reconstituted with wt bone marrow, and mixed chimera ± iRPs. Preliminary data in wt mice suggest that iRPs located in the spleen control bacteraemia in sepsis by inducing extramedullary myelopoiesis. Taken together, these experiments will elucidate how iRPs participate in sepsis. The insights may lead to new treatment strategies for sepsis and infection.