PUBLICATION

Inflammasome Regulates Hematopoiesis through Cleavage of the Master Erythroid Transcription Factor GATA1

Authors
Tyrkalska, S.D., Pérez-Oliva, A.B., Rodríguez-Ruiz, L., Martínez-Morcillo, F.J., Alcaraz-Pérez, F., Martínez-Navarro, F.J., Lachaud, C., Ahmed, N., Schroeder, T., Pardo-Sánchez, I., Candel, S., López-Muñoz, A., Choudhuri, A., Rossmann, M.P., Zon, L.I., Cayuela, M.L., García-Moreno, D., Mulero, V.
ID
ZDB-PUB-190609-2
Date
2019
Source
Immunity   51(1): 50-63.e5 (Journal)
Registered Authors
Mulero, Victor, Zon, Leonard I.
Keywords
Caspase-1, GATA1, Hematopoiesis, anemia, inflammasome, mouse, neutrophilic inflammation, zebrafish
MeSH Terms
  • Anemia/immunology*
  • Animals
  • Animals, Genetically Modified
  • Caspase 1/genetics
  • Caspase 1/metabolism
  • Cell Differentiation
  • Erythroid Cells/cytology
  • Fish Diseases/immunology*
  • GATA1 Transcription Factor/genetics
  • GATA1 Transcription Factor/metabolism*
  • Gene Expression Regulation, Developmental
  • Hematopoiesis
  • Humans
  • Inflammasomes/genetics
  • Inflammasomes/metabolism*
  • Inflammation/immunology*
  • K562 Cells
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils/immunology*
  • Proteolysis
  • Zebrafish/physiology*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
31174991 Full text @ Immunity
Abstract
Chronic inflammatory diseases are associated with altered hematopoiesis that could result in neutrophilia and anemia. Here we report that genetic or chemical manipulation of different inflammasome components altered the differentiation of hematopoietic stem and progenitor cells (HSPC) in zebrafish. Although the inflammasome was dispensable for the emergence of HSPC, it was intrinsically required for their myeloid differentiation. In addition, Gata1 transcript and protein amounts increased in inflammasome-deficient larvae, enforcing erythropoiesis and inhibiting myelopoiesis. This mechanism is evolutionarily conserved, since pharmacological inhibition of the inflammasome altered erythroid differentiation of human erythroleukemic K562 cells. In addition, caspase-1 inhibition rapidly upregulated GATA1 protein in mouse HSPC promoting their erythroid differentiation. Importantly, pharmacological inhibition of the inflammasome rescued zebrafish disease models of neutrophilic inflammation and anemia. These results indicate that the inflammasome plays a major role in the pathogenesis of neutrophilia and anemia of chronic diseases and reveal druggable targets for therapeutic interventions.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping