Induction of myelodysplasia by myeloid-derived suppressor cells

Abstract

Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33's immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif-bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

“…As we previously reported, 11 BM plasma concentration of S100A9 was significantly higher in LR-MDS patient specimens (n 5 33) than in controls (n 5 12; P 5 1.5 3 10 24 ) (Figure 2A). Analysis of S100A9 BM plasma concentration by IPSS risk category showed a 2.3-and 2.2-fold increase in low-risk (n 5 10, P 5 2.3 3 10 25 ) and intermediate I-risk MDSs (n 5 23, P 5 1.0 3 10 23 ) compared with normal controls (n 5 12), whereas there were no significant differences among controls and intermediate II-risk (n 5 17) or high-risk (n 5 10) disease ( Figure 2B).…”

“…11 Confocal fluorescence microscopy analyses of BM cells from the tibia and femurs of S100A9Tg vs wild-type (WT) mice at 2 (n 5 4), 6 (n 5 4), and 11 (n 5 5) months of age showed that caspase-1 activation increased with age in the BM cells of S100A9 transgenics, increasing 2.1-fold at 2 months, 2.4-fold at 6 months (P 5 3.3 3 10 23 ), and 2.5-fold at 11 months (P 5 .010). Similarly, in S100A9Tg mice, NLRP3 levels were increased 21.1-fold at 2 months (P 5 .059), 25.6-fold at 6 months (P 5 2.2 3 10 24 ), and 12.1-fold at 11 months (P 5 .018) ( Figure 5A).…”

“…9 Indeed, inflammatory cytokines such as interleukin-1b (IL-1b), tumor necrosis factor a, transforming growth factor b, IL-6, and others are generated in excess in MDSs, accompanied by BM expansion of hematopoietic-inhibitory, myeloid-derived suppressor cells (MDSCs) activated by the dangerassociated molecular pattern (DAMP) S100A9, a Toll-like receptor 4 (TLR4) and CD33 ligand. [10][11][12][13] Furthermore, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress TLRs, which is accompanied by activation of respective signaling intermediates and has been implicated in the aberrant proliferation of HSPCs and the pathogenesis of peripheral blood cytopenias. [14][15][16]NF-kB-induced transcriptional priming of inflammasome proteins, followed by cation channel activation, cell volume expansion, and inflammasome component assembly.…”

Autoimmune diseases and myelodysplastic syndromes

“…Myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, are markedly expanded in MDS bone marrow and contribute to the development of dysplasia and also possibly to cytopenias [12]. These cells are clonally distinct from the myeloid clone and overproduce hematopoietic suppressive inflammatory cytokines and mediators, such as arginase and nitric oxide [12]. MDSC expansion is driven by the production of a proinflammatory molecule (S100A9) that interacts with both the CD33 receptor and Toll-like receptor 4.…”

“…MDSC expansion is driven by the production of a proinflammatory molecule (S100A9) that interacts with both the CD33 receptor and Toll-like receptor 4. S100A9 transgenic mice display bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia [12]. The primary function of MDSCs is to dampen the response of autoreactive effector CD81 T-cells.…”