NOD2/CARD15 on bone marrow CD34+ hematopoietic cells mediates induction of cytokines and cell differentiation.

Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, HN-0310, Oslo, Norway.
Journal of leukocyte biology (Impact Factor: 4.99). 03/2009; 85(6):939-46. DOI: 10.1189/jlb.1008650
Source: PubMed

ABSTRACT Human bone marrow (BM) hematopoietic cells were found recently to express functional TLRs and TLR signaling-induced cytokine production and cell differentiation. Here, we have asked whether signals other than those from TLRs could instruct BM CD34+ cells to produce cytokines and differentiate by uncovering the role of nucleotide oligomerization domain (Nod)-like receptor (NLR) family members, NOD1 and NOD2. We show that NOD2 is expressed by freshly isolated human BM CD34+ cells, whereas the expression of its close homologue NOD1 is very weak. Stimulation of the cells by the muramyl dipeptide (MDP), but not its inactive D-D enantiomer, is sufficient to trigger the expression of TNF-alpha, GM-CSF, CD11c, CD14, CD206, and the transcription factor PU.1, which is indispensable for cell differentiation toward the myeloid lineage. MDP differentiated CD11c+ cell subset-activated T cells in MLR. Furthermore, NOD2 stimulation enhanced the CD34+ response to TLR ligands (e.g., LPS, palmitoyl-3-cysteine-serine-lysine-4) and increased intracellular alpha-defensin protein levels. Although the best-known function of NLRs involves mature cells, our data highlight for the first time the functionality of these receptors in human BM CD34+ hematopoietic cells.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Stem cells are cells that undergo self-renewal and can differentiate into multi-lineages. They are tightly regulated by their microenvironment via cell-to-cell contact and endogenous signals. With the recent discovery of Toll-like receptors (TLRs) on several types of stem cells it is possible that microbial ligands are able to influence stem cells. Indeed microbial ligands such as LPS and lipoproteins alter proliferation, differentiation, migration, and function of stem cells. In this report, I reviewed the effect of TLR activation on hematopoietic stem cells (HSCs) and multipotent stem cells (MSCs). In humans most TLRs activity does not seem to affect stem cell proliferation. In mice, however, stem cell proliferation is increased after TLR activation. Stem cell differentiation can also be regulated by TLR activation. Upon exposure to microbial ligands stem cells will change their differentiation to help the initial immune response. Activation of TLRs on MSCs increases osteogenesis and decreases adipogenesis and activation on HSCs increases myeloid differentiation and the production of monocytes/macrophages and DCs. Besides altering differentiation, TLR activation alters cytokine production by stem cells and the immunosuppressive function of MSCs. In general, TLR and NOD2 activation on stem cells increases the production of pro-inflammatory cytokines. However, some studies show an increase of anti-inflammatory cytokines. The response depends on ligand dose and exposure time but other factors such as micro-environment, co-stimulatory molecules, and downstream signaling pathways also influence cytokine production. The immunosuppressive function of MSCs can be increased or inhibited by TLR activation depending on the type of signaling pathways that are activated. With the identification of innate immune receptors on stem cells and the first findings that microbial ligands can influence stem cell fate, a whole new exciting area of research has been discovered.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Members of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family participate in the innate immune system, exerting widespread effects on cytokine secretion, autophagy, and apoptosis. Recent studies in Caucasians revealed the association between mutants of NOD2, a member of the NLR family, and severity of acute graft-versus-host disease (GVHD). NOD2 polymorphism screening has been recommended for donor selection and risk assessment at bone marrow transplantation. To investigate whether NOD2 plays a role in the pathogenesis of GVHD in a Japanese population, we examined DNA from 142 bone marrow transplant patient/donor pairs to detect genetic variation in the NOD2 gene. No genetic variants of NOD2 were associated with the severity of acute GVHD in our patients. However, a weak association between a single nucleotide polymorphism in the NOD2 gene (R471C) and acute myeloid leukemia in the bone marrow patients (p = 0.029, odds ratio 4.08, 95% CI 1.22-13.67) was detected. This polymorphism was not prevalent in 479 Crohn's disease (CD) patients in Japan. These results suggest that, in the Japanese population, unlike the Caucasian, NOD2 is not a major contributor to susceptibility to severe acute GVHD.
    International journal of hematology 06/2011; 93(6):771-8. · 1.17 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Eosinophils are multi-functional leucocytes that play a role in inflammatory processes including allergy and infection. Although bone marrow (BM) inflammatory cells are the main source of eosinophil-basophil (Eo/B) differentiation-inducing cytokines, a recent role has been demonstrated for cytokine induction through Toll-like receptor (TLR)-mediated signalling in BM progenitors. Having previously demonstrated that cord blood (CB) progenitors induce Eo/B colony-forming units (CFU) after lipopolysaccharide (LPS) stimulation, we sought to investigate the intracellular mechanisms by which LPS induces Eo/B differentiation. Freshly isolated CD34-enriched human CB cells were stimulated with LPS (and/or pharmacological inhibitors) and assessed for alterations in haematopoietic cytokine receptor expression and signalling pathways by flow cytometry, Eo/B CFU in methylcellulose cultures, and cytokine secretion using Luminex assays. The LPS stimulation resulted in a significant increase in granulocyte–macrophage colony-stimulating factor (GM-CSF)-responsive, as opposed to interleukin-5-responsive, Eo/B CFU, which also correlated with significant increases in CD34+ cell GM-CSFRα expression. Functionally, CB CD34+ cells secrete abundant amounts of GM-CSF following LPS stimulation, via a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism; this secretion was responsible for Eo/B CFU formation ex vivo, as shown by antibody blockade. We show for the first time that LPS stimulation of CB progenitor cells results in autocrine activation of p38 MAPK-dependent GM-CSF secretion facilitating Eo/B differentiation ex vivo. This work provides evidence that early life exposure to products of bacterial agents can modulate Eo/B differentiation, representing a novel mechanism by which progenitor cells can respond to microbial stimuli and so affect immune and inflammatory responses.
    Immunology 06/2013; 139(2). · 3.71 Impact Factor

Full-text (2 Sources)

Available from
Jun 4, 2014