Frontline Science: Myeloid cell‐specific deletion of Cebpb decreases sepsis‐induced immunosuppression in mice

• Published in: Journal of leukocyte biology Vol. 102; no. 2; pp. 191 - 200
• Main Authors: McPeak, Melissa B., Youssef, Dima, Williams, Danielle A., Pritchett, Christopher L., Yao, Zhi Q., McCall, Charles E., El Gazzar, Mohamed
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.08.2017; Society for Leukocyte Biology
• Subjects: Adaptive immunity; Adoptive transfer; Animal models; Animals; Blotting, Western; Bone marrow; CCAAT-Enhancer-Binding Protein-beta - immunology; CD11b antigen; Cell Differentiation - immunology; Clonal deletion; Colonies; Disease Models, Animal; Flow Cytometry; Growth factors; immune suppression; Immune system; Immune Tolerance - immunology; Immunity; Immunosuppression; Inflammation; Inflammation - immunology; Leukocytes (granulocytic); MDSC; Mice; Mice, Inbred BALB C; Mice, Knockout; microRNA; Monocytes; Myeloid cells; Myeloid-Derived Suppressor Cells - immunology; Myelopoiesis; Osteoprogenitor cells; Real-Time Polymerase Chain Reaction; Rodents; Sepsis; Sepsis - immunology; Spotlight on Leading Edge Research; Steady state; Suppressor cells; Target recognition; microRNA; MDSC; immune suppression; inflammation; sepsis
• ISSN: 0741-5400; 1938-3673; 1938-3673
• DOI: 10.1189/jlb.4HI1216-537R

Mechanisms by which C/EBPβ promotes sepsis‐induced immunosuppression. 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.