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Stem Cell Reports. 2016 Jun 14;6(6):940-956. doi: 10.1016/j.stemcr.2016.05.002. Epub 2016 Jun 2.

Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through Distinct Contributions of TRIF and MYD88.

Author information

1
Department of Medical and Molecular Genetics, School of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Herman B Wells Center for Pediatric Research, School of Medicine, Indiana University School of Medicine, 1044 West Walnut, Indianapolis, IN 46202, USA.
2
Herman B Wells Center for Pediatric Research, School of Medicine, Indiana University School of Medicine, 1044 West Walnut, Indianapolis, IN 46202, USA.
3
Department of Microbiology, School of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
4
Department of Medical and Molecular Genetics, School of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Herman B Wells Center for Pediatric Research, School of Medicine, Indiana University School of Medicine, 1044 West Walnut, Indianapolis, IN 46202, USA. Electronic address: ncarless@iu.edu.

Abstract

Toll-like receptor 4 (TLR4) plays a central role in host responses to bacterial infection, but the precise mechanism(s) by which its downstream signaling components coordinate the bone marrow response to sepsis is poorly understood. Using mice deficient in TLR4 downstream adapters MYD88 or TRIF, we demonstrate that both cell-autonomous and non-cell-autonomous MYD88 activation are major causes of myelosuppression during sepsis, while having a modest impact on hematopoietic stem cell (HSC) functions. In contrast, cell-intrinsic TRIF activation severely compromises HSC self-renewal without directly affecting myeloid cells. Lipopolysaccharide-induced activation of MYD88 or TRIF contributes to cell-cycle activation of HSC and induces rapid and permanent changes in transcriptional programs, as indicated by persistent downregulation of Spi1 and CebpA expression after transplantation. Thus, distinct mechanisms downstream of TLR4 signaling mediate myelosuppression and HSC exhaustion during sepsis through unique effects of MyD88 and TRIF.

PMID:
27264973
PMCID:
PMC4911503
DOI:
10.1016/j.stemcr.2016.05.002
[Indexed for MEDLINE]
Free PMC Article

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