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Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through
Distinct Contributions of TRIF and MYD88
#MMPMID27264973
Zhang H
; Rodriguez S
; Wang L
; Wang S
; Serezani H
; Kapur R
; Cardoso AA
; Carlesso N
Stem Cell Reports
2016[Jun]; 6
(6
): 940-956
PMID27264973
show ga
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.
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