PU.1 is required to restrain myelopoiesis during chronic inflammatory stress

Frontiers in Cell and Developmental Biology

Cell and Developmental Biology

Katia E. Niño¹  James S. Chavez¹  Harrison H. Wells¹  Giovanny Hernandez¹  Jennifer L. Rabe¹  Rachel L. Gessner¹  Taylor S. Mills²  Eric M. Pietras² 

[1] Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States;Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States;Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States;

关键词: hematopoiesis;    inflammation;    myelopoiesis;    PU.1;    hematopoietic stem cell;    hematopoietic progenitor cell;   

DOI  :  10.3389/fcell.2023.1204160

 received in 2023-04-11, accepted in 2023-06-19,  发布年份 2023

来源: Frontiers

【 摘 要 】

Chronic inflammation is a common feature of aging and numerous diseases such as diabetes, obesity, and autoimmune syndromes and has been linked to the development of hematological malignancy. Blood-forming hematopoietic stem cells (HSC) can contribute to these diseases via the production of tissue-damaging myeloid cells and/or the acquisition of mutations in epigenetic and transcriptional regulators that initiate evolution toward leukemogenesis. We previously showed that the myeloid “master regulator” transcription factor PU.1 is robustly induced in HSC by pro-inflammatory cytokines such as interleukin (IL)-1β and limits their proliferative activity. Here, we used a PU.1-deficient mouse model to investigate the broader role of PU.1 in regulating hematopoietic activity in response to chronic inflammatory challenges. We found that PU.1 is critical in restraining inflammatory myelopoiesis via suppression of cell cycle and self-renewal gene programs in myeloid-biased multipotent progenitor (MPP) cells. Our data show that while PU.1 functions as a key driver of myeloid differentiation, it plays an equally critical role in tailoring hematopoietic responses to inflammatory stimuli while limiting expansion and self-renewal gene expression in MPPs. These data identify PU.1 as a key regulator of “emergency” myelopoiesis relevant to inflammatory disease and leukemogenesis.

【 授权许可】

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Copyright © 2023 Chavez, Rabe, Niño, Wells, Gessner, Mills, Hernandez and Pietras.