title: Detection of a TLR2 agonist by hematopoietic stem and progenitor cells impacts the function of the macrophages they produce.
abstract: Several groups have shown that detection of microbial components by TLRs on hematopoietic stem and progenitor cells (HSPCs) instructs myeloid cell generation, raising interest in the possibility of targeting TLRs on HSPCs to boost myelopoiesis. However, although "TLR-derived" cells exhibit myeloid cell characteristics (phagocytosis, cytokine production, antigen presentation), it is not clear whether they are functionally equivalent to macrophages derived in the absence of TLR activation. Our in vitro and in vivo studies show that macrophages derived from mouse and human HSPC subsets (including stem cells) exposed to a TLR2 agonist prior to or during macrophage differentiation produce lower levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and reactive oxygen species. This is in contrast to prior exposure of differentiated macrophages to the TLR2 agonist ("tolerance"), which suppresses inflammatory cytokine production, but elevates reactive oxygen species. Soluble factors produced following exposure of HSPCs to a TLR2 agonist can also act in a paracrine manner to influence the function of macrophages derived from unexposed HSPCs. Our data demonstrate that macrophage function can be influenced by TLR signaling in the HSPCs from which they are derived, and that this may impact the clinical utility of targeting TLRs on HSPCs to boost myelopoiesis.
authors: Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Alberto
authors: A
authors: Yáñez
authors: Nargess
authors: N
authors: Hassanzadeh-Kiabi
authors: Madelena Y
authors: MY
authors: Ng
authors: Javier
authors: J
authors: Megías
authors: Aparna
authors: A
authors: Subramanian
authors: George Y
authors: GY
authors: Liu
authors: David M
authors: DM
authors: Underhill
authors: M Luisa
authors: ML
authors: Gil
authors: Helen S
authors: HS
authors: Goodridge
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D055666:Lipopeptides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells; D038042:Myelopoiesis; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D017382:Reactive Oxygen Species; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha
keywords: Hematopoietic progenitor cells; Hematopoietic stem cells; Monocytes/ macrophages; Myelopoiesis; TLRs
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