Hematopoietic crippling by chronic TLR4 ligand requires cell-intrinsic TLR4 and compromises both murine and human HSPCs in vivo (HEM5P.227)

Abstract The classical model for blood cell replenishment is changing with the unexpected realization that hematopoietic stem and progenitor cells (HSPCs) directly sense and respond to pathogens via toll-like receptors (TLRs). For the first time, we show that human HSPCs are severely compromised by repeated exposure to low dose TLR4 ligand as assessed in vivo in humanized mice. CD34+ HSPCs are reduced 50% with concomitant hyperproliferation. Downstream bone marrow lymphoid precursors and peripheral B cells are virtually ablated to the benefit of the myeloid cells. In the mouse model, reciprocal chimeras reveal that numerical and functional hematopoietic stem cell (HSC) defects following repeated exposure to TLR4 ligand require hematopoietic-derived TLR4. Selective deficiency of TLR4 on hematopoietic cells alleviates HSC hyperproliferation and myeloid skewing while cell non-autonomous TLR4 is largely dispensable. Finally, within uncommitted progenitor compartments, we show that HSC and downstream non-renewing multipotent progenitors (MPP) respond directly to TLR4 ligand. Thus, while transient TLR stimulation is thought to enable replenishment of the innate immune compartments that are rapidly consumed through acute infection, chronic TLR stimulation is detrimental to both murine and human HSPC integrity in vivo. These findings have broad implications as persistent exposure to TLR4 ligand occurs in individuals suffering from each chronic infection and obesity.