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: 4.29). 03/2009; 85(6):939-46. DOI: 10.1189/jlb.1008650
Source: PubMed


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.

Download full-text


Available from: Mouldy Sioud
  • Source
    • "Early functional studies identified NOD2 expression in antigen-presenting cells, specifically intestinal epithelial cells [27], Paneth cells [28] [29], macrophages, and dendritic cells [21]. An increasing number of studies have demonstrated that NOD2 is expressed in a multitude of tissues including keratinocytes [30], T cells [31], NK cells, and CD34+ bone marrow stem cells [32] [33]. NOD2 is expressed within the cytosol and can be recruited to the cell membrane of intestinal epithelial cells [34] [35], a mechanism that appears to be important in the function of the molecule. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Haematopoietic stem cell transplantation (HSCT) is a valuable tool in the treatment of many haematological disorders. Advances in understanding HLA matching have improved prognoses. However, many recipients of well-matched HSCT develop posttransplant complications, and survival is far from absolute. The pursuit of novel genetic factors that may impact on HSCT outcome has resulted in the publication of many articles on a multitude of genes. Three NOD2 polymorphisms, identified as disease-associated variants in Crohn's disease, have recently been suggested as important candidate gene markers in the outcome of HSCT. It was originally postulated that as the clinical manifestation of inflammatory responses characteristic of several post-transplant complications was of notable similarity to those seen in Crohn's disease, it was possible that they shared a common cause. Since the publication of this first paper, numerous studies have attempted to replicate the results in different transplant settings. The data has varied considerably between studies, and as yet no consensus on the impact of NOD2 SNPs on HSCT outcome has been achieved. Here, we will review the existing literature, summarise current theories as to why the data differs, and suggest possible mechanisms by which the SNPs affect HSCT outcome.
    Full-text · Article · Oct 2012
  • Source
    • "After stimulation with S. aureus CD34+ HSPC produced high levels of TNF, IL-6, IL-8, IL-23, and IL-10 [85]. Upon ligation of NOD2 by MDP, human CD34+ cells expressed TNFα, IL-1β, and GM-CSF [78]. They also upregulated intracellular stores of α-defensins 1–3, suggesting that they may be able to directly fight bacterial infections [78]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent research has shed light on novel functions of hematopoietic stem and progenitor cells (HSPC). While they are critical for maintenance and replenishment of blood cells in the bone marrow, these cells are not limited to the bone marrow compartment and function beyond their role in hematopoiesis. HSPC can leave bone marrow and circulate in peripheral blood and lymph, a process often manipulated therapeutically for the purpose of transplantation. Additionally, these cells preferentially home to extramedullary sites of inflammation where they can differentiate to more mature effector cells. HSPC are susceptible to various pathogens, though they may participate in the innate immune response without being directly infected. They express pattern recognition receptors for detection of endogenous and exogenous danger-associated molecular patterns and respond not only by the formation of daughter cells but can themselves secrete powerful cytokines. This paper summarizes the functional and phenotypic characterization of HSPC, their niche within and outside of the bone marrow, and what is known regarding their role in the innate immune response.
    Full-text · Article · Jun 2012
  • Source
    • "NOD2 is expressed in skin and in keratinocytes, and recognize peptidoglycan fragments, e.g., muramyl dipeptide, resulting in increased expression of β-defensin 2 and various cytokines (Voss et al., 2006; Siod and Flø, 2009). Also, NOD2 has been suggested to play a role in the activation of some types of inflammasomes (Martinon et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Staphylococcus aureus may cause serious skin and soft tissue infections, deep abscesses, endocarditis, osteomyelitis, pneumonia, and sepsis. S. aureus persistently colonizes 25-30% of the adult human population, and S. aureus carriers have an increased risk for infections caused by the bacterium. The major site of colonization is the nose, i.e., the vestibulum nasi, which is covered with ordinary skin and hair follicles. Several host and microbe determinants are assumed to be associated with colonization. These include the presence and expression level of bacterial adhesins, which can adhere to various proteins in the extracellular matrix or on the cellular surface of human skin. The host expresses several antimicrobial peptides and lipids. The level of β-defensin 3, free sphingosine, and cis-6-hexadecenoic acid are found to be associated with nasal carriage of S. aureus. Other host factors are certain polymorphisms in Toll-like receptor 2, mannose-binding lectin, C-reactive protein, glucocorticoid-, and vitamin D receptor. Additional putative determinants for carriage include genetic variation and expression of microbial surface components recognizing adhesive matrix molecules and their interaction partners, as well as variation among humans in the ability of recognizing and responding appropriately to the bacteria. Moreover, the available microflora may influence the success of S. aureus colonization. In conclusion, colonization is a complex interplay between the bacteria and its host. Several bacterial and host factors are involved, and an increased molecular understanding of these are needed.
    Full-text · Article · May 2012 · Frontiers in Cellular and Infection Microbiology
Show more