Hematopoietic stem cell expansion and common lymphoid progenitor depletion requires hematopoietic-derived cell-autonomous TLR4 in a model of chronic endotoxin

摘要

Hematopoietic stem and progenitors cells (HSPCs) are activated through toll-like receptor 4 (TLR4) in vitro. However, it remains unclear whether in vivo TLR4 sensing by HSPCs occurs directly or via other cell intermediates. Here, we examine the cellular mechanisms underlying murine hematopoietic stem cell (HSC) expansion and common lymphoid progenitor (CLP) depletion in a model of chronic low-dose lipopolysaccharide (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 pre-clinical 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.