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

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

Williams, Danielle A.¹  El Gazzar, Mohamed²  Yao, Zhi Q.²  Pritchett, Christopher L.³  McCall, Charles E.³  Youssef, Dima⁴ 

[1] and;Department of Health Sciences, College of Public Health, East Tennessee State University Johnson City, Tennessee, USA;Department of Internal Medicine, College of Medicine, East Tennessee State University Johnson City, Tennessee, USA;Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston‐Salem, North Carolina, USA

关键词: sepsis;    inflammation;    immune suppression;    MDSC;    microRNA;   

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

CC BY