Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through Distinct Contributions of TRIF and MYD88.
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.
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.
Huajia
H
Zhang
Herman B Wells Center for Pediatric Research, School of Medicine, Indiana University School of Medicine, 1044 West Walnut, Indianapolis, IN 46202, USA.
Sonia
S
Rodriguez
Herman B Wells Center for Pediatric Research, School of Medicine, Indiana University School of Medicine, 1044 West Walnut, Indianapolis, IN 46202, USA.
Lin
L
Wang
Department of Microbiology, School of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Soujuan
S
Wang
Department of Microbiology, School of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Henrique
H
Serezani
Herman B Wells Center for Pediatric Research, School of Medicine, Indiana University School of Medicine, 1044 West Walnut, Indianapolis, IN 46202, USA.
Reuben
R
Kapur
Herman B Wells Center for Pediatric Research, School of Medicine, Indiana University School of Medicine, 1044 West Walnut, Indianapolis, IN 46202, USA.
Angelo A
AA
Cardoso
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.
Nadia
N
Carlesso
D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000276:immunology; D002453:Cell Cycle; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology*; D008070:Lipopolysaccharides; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology*; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1
D033942:Adaptor Proteins, Vesicular Transport; D022762:CCAAT-Enhancer-Binding Proteins; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D011518:Proto-Oncogene Proteins; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C530718:CEBPA protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse