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

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2016 Jun 7

PMID 27264973

Citations 59

Authors

Huajia Zhang

Sonia Rodriguez

Lin Wang

Soujuan Wang

Henrique Serezani

Reuben Kapur

Angelo A Cardoso

Nadia Carlesso

Affiliations

Soon will be listed here.

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.

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References

Carson W, Cavassani K, Dou Y, Kunkel S . Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics. 2010; 6(3):273-83. PMC: 3092675. DOI: 10.4161/epi.6.3.14017. View

Staber P, Zhang P, Ye M, Welner R, Nombela-Arrieta C, Bach C . Sustained PU.1 levels balance cell-cycle regulators to prevent exhaustion of adult hematopoietic stem cells. Mol Cell. 2013; 49(5):934-46. PMC: 3644723. DOI: 10.1016/j.molcel.2013.01.007. View

Poltorak A, He X, Smirnova I, Liu M, Van Huffel C, Du X . Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998; 282(5396):2085-8. DOI: 10.1126/science.282.5396.2085. View

Wilson A, Laurenti E, Oser G, van der Wath R, Blanco-Bose W, Jaworski M . Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008; 135(6):1118-29. DOI: 10.1016/j.cell.2008.10.048. View

Opal S, Laterre P, Francois B, LaRosa S, Angus D, Mira J . Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013; 309(11):1154-62. DOI: 10.1001/jama.2013.2194. View

Miyamoto T, Iwasaki H, Reizis B, Ye M, Graf T, Weissman I . Myeloid or lymphoid promiscuity as a critical step in hematopoietic lineage commitment. Dev Cell. 2002; 3(1):137-47. DOI: 10.1016/s1534-5807(02)00201-0. View

Baldridge M, King K, Boles N, Weksberg D, Goodell M . Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature. 2010; 465(7299):793-7. PMC: 2935898. DOI: 10.1038/nature09135. View

Essers M, Offner S, Blanco-Bose W, Waibler Z, Kalinke U, Duchosal M . IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009; 458(7240):904-8. DOI: 10.1038/nature07815. View

Angus D . The search for effective therapy for sepsis: back to the drawing board?. JAMA. 2011; 306(23):2614-5. DOI: 10.1001/jama.2011.1853. View

10.

Weighardt H, Jusek G, Mages J, Lang R, Hoebe K, Beutler B . Identification of a TLR4- and TRIF-dependent activation program of dendritic cells. Eur J Immunol. 2004; 34(2):558-64. DOI: 10.1002/eji.200324714. View

11.

Bosmann M, Ward P . The inflammatory response in sepsis. Trends Immunol. 2012; 34(3):129-36. PMC: 3543471. DOI: 10.1016/j.it.2012.09.004. View

12.

Bradfute S, Graubert T, Goodell M . Roles of Sca-1 in hematopoietic stem/progenitor cell function. Exp Hematol. 2005; 33(7):836-43. DOI: 10.1016/j.exphem.2005.04.001. View

13.

Rodriguez S, Chora A, Goumnerov B, Mumaw C, Goebel W, Fernandez L . Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. Blood. 2009; 114(19):4064-76. PMC: 2774548. DOI: 10.1182/blood-2009-04-214916. View

14.

Vincent J, Rello J, Marshall J, Silva E, Anzueto A, Martin C . International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009; 302(21):2323-9. DOI: 10.1001/jama.2009.1754. View

15.

Esplin B, Shimazu T, Welner R, Garrett K, Nie L, Zhang Q . Chronic exposure to a TLR ligand injures hematopoietic stem cells. J Immunol. 2011; 186(9):5367-75. PMC: 3086167. DOI: 10.4049/jimmunol.1003438. View

16.

Weighardt H, Kaiser-Moore S, Vabulas R, Kirschning C, Wagner H, Holzmann B . Cutting edge: myeloid differentiation factor 88 deficiency improves resistance against sepsis caused by polymicrobial infection. J Immunol. 2002; 169(6):2823-7. DOI: 10.4049/jimmunol.169.6.2823. View

17.

Pietras E, Lakshminarasimhan R, Techner J, Fong S, Flach J, Binnewies M . Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J Exp Med. 2014; 211(2):245-62. PMC: 3920566. DOI: 10.1084/jem.20131043. View

18.

Challen G, Sun D, Jeong M, Luo M, Jelinek J, Berg J . Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet. 2011; 44(1):23-31. PMC: 3637952. DOI: 10.1038/ng.1009. View

19.

Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H . Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003; 301(5633):640-3. DOI: 10.1126/science.1087262. View

20.

van Lieshout M, Blok D, Wieland C, de Vos A, Veer C, van der Poll T . Differential roles of MyD88 and TRIF in hematopoietic and resident cells during murine gram-negative pneumonia. J Infect Dis. 2012; 206(9):1415-23. DOI: 10.1093/infdis/jis505. View