Tyrkalska SD, Pérez-Oliva AB, Rodríguez-Ruiz L, Martínez-Morcillo FJ, Alcaraz-Pérez F, Martínez-Navarro FJ, Lachaud C, Ahmed N, Schroeder T, Pardo-Sánchez I, Candel S, López-Muñoz A, Choudhuri A, Rossmann MP, Zon LI, Cayuela ML, García-Moreno D, Mulero V. 2019. Inflammasome Regulates Hematopoiesis through Cleavage of the Master Erythroid Transcription Factor GATA1. Immunity. 51(1):50-63.e5. Pubmed: 31174991 DOI:S1074-7613(19)30225-0


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.
Copyright © 2019 Elsevier Inc. All rights reserved.

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The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.

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