Research Paper Volume 11, Issue 21 pp 9626—9642

Cellular senescence induced by S100A9 in mesenchymal stromal cells through NLRP3 inflammasome activation

Lei Shi 1, *, , Youshan Zhao 1, *, , Chengming Fei 1, , Juan Guo 1, , Yan Jia 1, , Dong Wu 1, , Lingyun Wu 1, , Chunkang Chang 1, ,

  • 1 Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
* Equal contribution

received: August 12, 2019 ; accepted: October 26, 2019 ; published: November 14, 2019 ;

https://doi.org/10.18632/aging.102409
How to Cite

Copyright © 2019 Shi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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-27a 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-27a 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-1β supplementation 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.

Abbreviations

MDS: Myelodysplastic syndrome; MSC: Mesenchymal stromal cells; TLR4: Toll-like receptor 4; ROS: Reactive oxygen species; BM-MNC: Bone marrow mononuclear cells.