Frontline Science: Myeloid cell-specific deletion of Cebpb decreases sepsis-induced immunosuppression in mice.
Sepsis inflammation accelerates myeloid cell generation to compensate for rapid mobilization of the myeloid progenitors from bone marrow. This inflammation-driven myelopoiesis, however, generates myeloid progenitors with immunosuppressive functions that are unable to differentiate into mature, innate immune cells. The myeloid-derived suppressor cells (MDSCs) expand markedly in the later phases of sepsis, suppress both innate and adaptive immunity, and thus, elevate mortality. Using a murine model with myeloid-restricted deletion of the C/EBPβ transcription factor, we show that sepsis-induced generation of MDSCs depends on C/EBPβ. C/EBPβ myeloid cell-deficient mice did not generate MDSCs or develop immunosuppression and survived sepsis. However, septic mice still generated Gr1+CD11b+ myeloid progenitors at the steady-state levels similar to the control sham mice, suggesting that C/EBPβ is not involved in healthy, steady-state myelopoiesis. C/EBPβ-deficient Gr1+CD11b+ cells generated fewer monocyte- and granulocyte-like colonies than control mice did, indicating reduced proliferation potential, but differentiated normally in response to growth factors. Adoptive transfer of C/EBPβ-deficient Gr1+CD11b+ cells from late septic mice exacerbated inflammation in control mice undergoing early sepsis, confirming they were not immunosuppressive. These results show that C/EBPβ directs a switch from proinflammatory to repressor myeloid cells and identifies a novel treatment target.
['McPeak|Melissa B|MB|', 'Youssef|Dima|D|', 'Williams|Danielle A|DA|', 'Pritchett|Christopher L|CL|', 'Yao|Zhi Q|ZQ|', 'McCall|Charles E|CE|', 'El Gazzar|Mohamed|M|']
D000818:Animals D015153:Blotting, Western D022782:CCAAT-Enhancer-Binding Protein-beta D002454:Cell Differentiation D004195:Disease Models, Animal D005434:Flow Cytometry D007108:Immune Tolerance D007249:Inflammation D051379:Mice D008807:Mice, Inbred BALB C D018345:Mice, Knockout D000072737:Myeloid-Derived Suppressor Cells D060888:Real-Time Polymerase Chain Reaction D018805:Sepsis
sepsis inflammation MDSC immune suppression microRNA