Collectively, these data suggest a model in which TLR1/2 stimulation of DCs induces secretion of IL-1β and other inflammatory cytokines into the perivascular niche, which in turn, regulates multipotent HSPCs. Single-cell RNA-sequencing of low-risk myelodysplastic syndrome bone marrow revealed that IL1B and TLR1 expression is increased in DCs.

Systemic TLR1/2 agonist treatment of Il1r1 −/− mice show that TLR1/2-induced HSPC expansion is dependent on IL-1β signaling. Interleukin-1β (IL-1β) is constitutively expressed in both murine and human DCs and is further induced after TLR1/2 stimulation. TLR1/2 agonist treatment of mice in which Myd88 is deleted specifically in DCs using Zbtb46-Cre show that the TLR1/2-induced expansion of multipotent HPSCs, but not HSPC mobilization or alterations in the bone marrow microenvironment, is dependent on TLR1/2 signaling in DCs.

It also induces marked alterations in the bone marrow microenvironment, including a decrease in osteoblast activity and sinusoidal endothelial cell numbers. Systemic treatment with a TLR1/2 agonist induces HSPC expansion and mobilization. Here, we show that perivascular bone marrow dendritic cells (DCs) express a high basal level of Toll-like receptor-1 (TLR1) and TLR2.

How these cues are transmitted to HSPCs within hematopoietic niches is not well established. A fundamental property of hematopoiesis is the ability to respond to environmental cues such as inflammation. Hematopoietic stem/progenitor cells (HSPCs) reside in localized microenvironments, or niches, in the bone marrow that provide key signals regulating their activity.

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