Cutting Edge: Hematopoietic Stem Cell Expansion and Common Lymphoid Progenitor Depletion Require Hematopoietic-Derived, Cell-Autonomous TLR4 in a Model of Chronic Endotoxin.
Hematopoietic stem and progenitors cells (HSPCs) are activated through TLR4 in vitro. However, it remains unclear whether in vivo TLR4 sensing by HSPCs occurs directly or via other cell intermediates. In this study, we examined the cellular mechanisms underlying murine hematopoietic stem cell (HSC) expansion and common lymphoid progenitor (CLP) depletion in a model of chronic low-dose LPS. Using adoptive-transfer approaches, we show that HSC and CLP sensitivity to chronic LPS depends on hematopoietic-derived, cell subset-autonomous TLR4. Like murine progenitors, human HSPCs are activated by TLR4 in vitro. Using humanized mice, a preclinical model relevant to human physiology, we show that persistent endotoxin increases the frequency of Ki-67(+) HSCs and severely depletes CLPs and B precursors. Together, our findings show that murine HSPCs directly respond to endotoxin in vivo and that persistent LPS, a feature of several diseases of global health significance, impairs human lymphopoiesis.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
Ailing
A
Liu
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
Yujuan
Y
Wang
Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261; and.
Ying
Y
Ding
Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA 92350.
Ineavely
I
Baez
Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA 92350.
Kimberly J
KJ
Payne
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; borghesi@pitt.edu.
Lisa
L
Borghesi
D019264:Adoptive Transfer; D000818:Animals; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D005312:Fetal Blood; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008212:Lymphocyte Depletion; D054503:Lymphoid Progenitor Cells / Q000276:immunology* / Q000378:metabolism; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D051197:Toll-Like Receptor 4 / Q000276:immunology*
D019394:Ki-67 Antigen; D008070:Lipopolysaccharides; C498355:Mki67 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4