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

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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.