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Updated: Mar 13, 2026
Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
Published on: May 21, 2018
The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype
Ashley A Basiorka1, Kathy L McGraw2, Erika A Eksioglu3
1Cancer Biology Ph.D. Program, Department of Malignant Hematology.
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.
Insights
Myelodysplastic syndromes (MDSs) feature an overactive NLRP3 inflammasome, driving cell death and ineffective blood cell production. Targeting this pathway with S100A9 neutralization or NLRP3/NOX inhibition restores normal hematopoiesis.
Area of Science:
- Immunology
- Hematology
- Cell Biology
Background:
- Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic stem cell disorders.
- MDSs are characterized by ineffective hematopoiesis and cytological dysplasia.
- A common pathway driving MDS pathogenesis remains elusive.
Purpose of the Study:
- To investigate the role of inflammasome activation in MDS pathogenesis.
- To identify molecular mechanisms linking genetic mutations to MDS phenotypes.
- To explore potential therapeutic targets for MDS.
Main Methods:
- Analysis of NLRP3 inflammasome components and activation in MDS hematopoietic stem and progenitor cells (HSPCs).
- Assessment of pyroptosis, reactive oxygen species (ROS) generation, and β-catenin signaling.
- Evaluation of therapeutic interventions including gene knockdown, alarmin neutralization, and pharmacologic inhibition.
Main Results:
- MDS HSPCs exhibit overexpression of inflammasome proteins and activated NLRP3 complexes, leading to pyroptosis.
- The alarmin S100A9 triggers pyroptosis via NADPH oxidase (NOX)-mediated ROS production and β-catenin activation.
- Inhibition of NLRP3, caspase-1, S100A9, or NOX suppressed pyroptosis and ROS, restoring effective hematopoiesis.
Conclusions:
- NLRP3 inflammasome activation is a central mechanism in MDS pathogenesis, independent of specific genetic mutations.
- A common redox-sensitive inflammasome circuit involving alarmins and founder gene mutations drives MDS.
- Targeting the NLRP3 inflammasome pathway presents a promising therapeutic strategy for MDS.
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