ANA BELEN PEREZ OLIVA¹, Sylwia Dominika Tyrkalska², Lola Rodríguez Ruiz¹, Juan Manuel Lozano Gil¹, MARIA LUISA CAYUELA FUENTES³, Diana García Moreno³, Victoriano Mulero Méndez¹

(1) INMUNIDAD, INFLAMACIÓN Y CÁNCER, IMIB-Arrixaca, España
(2)
(3) CIRUGÍA DIGESTIVA, ENDOCRINA Y TRASPLANTE DE ÓRGANOS ABDOMINALES, IMIB-Arrixaca, España

Chronic inflammatory diseases are associated to altered hematopoiesis that could result in neutrophilia and anemia. In this work we provide evidence of an evolutionary conserved mechanism by which inflammasome regulates the erythroid/myeloid decision in HSC, which might contribute to the hematopoietic bias of these diseases.

From genetic to pharmacological inhibitions in vitro and in vivo zebrafish model were used to study the role of the inflammasome regulating hematopoiesis. CRISPR-Cas9, western blot and immunoprecipitation and qPCR were used to complete the study as well as immunofluorescence and in vitro caspase activity.

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.