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

Zhang H, Rodriguez S, Wang L, Wang S, Serezani H, Kapur R, Cardoso AA, Carlesso N
Stem Cell Reports. 2016 6 (6): 940-956

PMID: 27264973 · PMCID: PMC4911503 · DOI:10.1016/j.stemcr.2016.05.002

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.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

MeSH Terms (18)

Adaptor Proteins, Vesicular Transport Animals CCAAT-Enhancer-Binding Proteins Cell Cycle Disease Models, Animal Gene Expression Regulation Hematopoietic Stem Cells Lipopolysaccharides Mice Mice, Knockout Myeloid Cells Myeloid Differentiation Factor 88 Proto-Oncogene Proteins Sepsis Signal Transduction Toll-Like Receptor 4 Trans-Activators Transcription, Genetic

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