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

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.