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Immunity. 2019 Jul 16;51(1):50-63.e5. doi: 10.1016/j.immuni.2019.05.005. Epub 2019 Jun 4.

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

Author information

1
Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
2
Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain. Electronic address: anabpo@um.es.
3
Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain.
4
Aix-Marseille University, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Marseille, France.
5
Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
6
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA.
7
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
8
Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain. Electronic address: dianagm@um.es.
9
Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain. Electronic address: vmulero@um.es.

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.

KEYWORDS:

Caspase-1; GATA1; Hematopoiesis; anemia; inflammasome; mouse; neutrophilic inflammation; zebrafish

PMID:
31174991
PMCID:
PMC6886364
DOI:
10.1016/j.immuni.2019.05.005
[Indexed for MEDLINE]
Free PMC Article

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