Sepsis induces hematopoietic stem cell exhaustion and myelosuppression through distinct contributions of TRIF and MYD88

Huajia Zhang, Sonia Rodriguez, Lin Wang, Soujuan Wang, Henrique Serezani, Reuben Kapur, Angelo A. Cardoso, Nadia Carlesso

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)940-956
Number of pages17
JournalStem Cell Reports
Volume6
Issue number6
DOIs
StatePublished - Jun 14 2016

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Hematopoietic Stem Cells
Stem cells
Toll-Like Receptor 4
Sepsis
Chemical activation
Myeloid Cells
Bacterial Infections
Lipopolysaccharides
Cell Cycle
Bone
Down-Regulation
Transplantation
Bone Marrow
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Developmental Biology
  • Genetics

Cite this

Sepsis induces hematopoietic stem cell exhaustion and myelosuppression through distinct contributions of TRIF and MYD88. / Zhang, Huajia; Rodriguez, Sonia; Wang, Lin; Wang, Soujuan; Serezani, Henrique; Kapur, Reuben; Cardoso, Angelo A.; Carlesso, Nadia.

In: Stem Cell Reports, Vol. 6, No. 6, 14.06.2016, p. 940-956.

Research output: Contribution to journalArticle

Zhang, Huajia ; Rodriguez, Sonia ; Wang, Lin ; Wang, Soujuan ; Serezani, Henrique ; Kapur, Reuben ; Cardoso, Angelo A. ; Carlesso, Nadia. / Sepsis induces hematopoietic stem cell exhaustion and myelosuppression through distinct contributions of TRIF and MYD88. In: Stem Cell Reports. 2016 ; Vol. 6, No. 6. pp. 940-956.
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AU - Kapur, Reuben

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AU - Carlesso, Nadia

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