Toll-like Receptors on Hematopoietic Progenitor Cells Stimulate Innate Immune System Replenishment

Abstract

Toll-like receptors (TLRs) are best known for their ability to recognize microbial or viral components and initiate innate immune responses. We showed here that TLRs and their coreceptors were expressed by multipotential hematopoietic stem cells, whose cell cycle entry was triggered by TLR ligation. TLR expression also extended to some of the early hematopoietic progenitors, although not the progenitor cells dedicated to megakaryocyte and erythroid differentiation. TLR signaling via the Myd88 adaptor protein drove differentiation of myeloid progenitors, bypassing some normal growth and differentiation requirements, and also drove lymphoid progenitors to become dendritic cells. CD14 contributed to the efficiency of lipopolysaccharide (LPS) recognition by stem and progenitor cells, and LPS interacted directly with the TLR4/MD-2 complex on these cells in bone marrow. Thus, the preferential pathogen-mediated stimulation of myeloid differentiation pathways may provide a means for rapid replenishment of the innate immune system during infection.

Innate immunity as orchestrator of stem cell mobilization

“…28,61 Mobilization could also be achieved by the administration of some types of polysaccharides (for example, zymosan or fucoidans) that in animal models have been demonstrated to efficiently mobilize HSPCs within 1 h after a single injection. 66,67 Elements of innate immunity involved in stem cell mobilization Evidence from our, [41][42][43][44]68 and other laboratories 69,70 indicates that innate immunity orchestrates egress of HSPCs from BM into PB. Innate or natural immunity is inborn and thus naturally present in an organism; it does not require previous sensitization to an antigen.…”

The TLR1/2 agonist PAM3CSK4 instructs commitment of human hematopoietic stem cells to a myeloid cell fate

“…1,15 However, only slight changes of the expression of PU.1 were reported for murine HSCs stimulated by TLRs, despite their massive differentiation into macrophages. 11 The possibility that low levels of endogenous PU.1 in HSCs may allow activation of the myelomonocytic program when C/EBPa is in excess is worth considering, because the enforced expression of C/EBPa is sufficient to reprogram mouse B cells to become macrophages. 30 There is evidence that adjacent cells and local cytokines contribute to the decision of stem cells to differentiate rather than to undergo self-renewal.…”

“…Nagai and colleagues have recently shown that TLR agonists promote the engagement of murine HSCs and early HPCs into the myeloid developmental path. 11 Two recent studies by Sioud et al have documented that TLRs are also expressed on human cord blood CD34 þ cells and that TLR ligands (TLR-L) can favor their differentiation into mature functional myeloid cells belonging either to the monocytic or dendritic cell (DC) lineages. 12,13 In this survey, we report that human HSCs and lineage-committed progenitors express a comparable TLR expression profile.…”

Toll-like receptor 4-mediated signaling regulates IL-7-driven proliferation and differentiation of B-cell precursors

“…In one report, LPS was shown to exert an inhibitory effect on B lymphopoiesis by promoting myeloid differentiation of hematopoietic progenitors through a Myd88-dependent mechanism. 13 A more recent study, however, indicates that LPS may facilitate B-cell maturation by acting as an accessory stimulus to complement the BAFF physiological pathway of B-cell development. 14 Therefore, the precise role of TLR4 signaling in the early stages of B-cell development requires more in-depth analysis.…”