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

Ashley A. Basiorka, Kathy L. McGraw, Erika A. Eksioglu, Xianghong Chen, Joseph Johnson, Ling Zhang, Qing Zhang, Brittany A. Irvine, Thomas Cluzeau, David A. Sallman, Eric Padron, Rami Komrokji, Lubomir Sokol, Rebecca C. Coll, Avril A.B. Robertson, Matthew A. Cooper, John L. Cleveland, Luke A. O'Neill, Sheng Wei, Alan F. List*

*Corresponding author for this work

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and β-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention.

Original languageEnglish
Pages (from-to)2960-2975
JournalBlood
Volume128
Issue number25
DOIs
Publication statusPublished - 22 Dec 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Basiorka, A. A., McGraw, K. L., Eksioglu, E. A., Chen, X., Johnson, J., Zhang, L., Zhang, Q., Irvine, B. A., Cluzeau, T., Sallman, D. A., Padron, E., Komrokji, R., Sokol, L., Coll, R. C., Robertson, A. A. B., Cooper, M. A., Cleveland, J. L., O'Neill, L. A., Wei, S., & List, A. F. (2016). The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood, 128(25), 2960-2975. https://doi.org/10.1182/blood-2016-07-730556