Cellular Senescence Induced By S100A9 In Mesenchymal Stromal Cells Through NLRP3 Inflammasome Activation In Myelodysplastic Syndromes

Bone marrow stromal cells from patients with myelodysplastic syndrome(MDS)display a senescence phenotype,but the underlying mechanism has not been elucidated.Pro-inflammatory signaling within the malignant clone and the bone marrow microenvironment has been identified as a key pathogenetic driver of MDS.Our study revealed that S100A9 is highly-expressed in lower-risk MDS.Moreover,normal primary mesenchymal stromal cells(MSCs)and the human stromal cell line HS-27 a co-cultured with lower-risk MDS bone marrow mononuclear cells acquired a senescence phenotype.Exogenous supplemented S100A9 also induced cellular senescence in MSCs and HS-27 a cells.Importantly,Toll-like receptor 4(TLR4)inhibition or knockdown attenuated the cellular senescence induced by S100A9.Furthermore,we showed that S100A9 induces NLRP3 inflammasome formation,and IL-1β secretion;findings in samples from MDS patients further confirmed these thoughts.Moreover,ROS and IL-1β inhibition suppressed the cellular senescence induced by S100A9,whereas NLRP3 overexpression and exogenous IL-1βsupplementation induces cellular senescence.Our study demonstrated that S100A9 promotes cellular senescence of bone marrow stromal cells via TLR4,NLRP3 inflammasome formation,and IL-1β secretion for its effects.Our findings deepen the understanding of the molecular mechanisms involved in MDS reprogramming of MSCs and indicated the essential role of S100A9 in tumor-environment interactions in bone marrow.