ATG5 promotes eosinopoiesis, but inhibits eosinophil effector functions.

Germic, Nina; Hosseini, Aref; Stojkov, Darko; Oberson, Kevin; Claus, Meike; Benarafa, Charaf; Calzavarini, Sara; Angelillo-Scherrer, Anne; Arnold, Isabelle C; Müller, Anne; Riether, Carsten; Yousefi, Shida; Simon, Hans-Uwe (2021). ATG5 promotes eosinopoiesis, but inhibits eosinophil effector functions. Blood, 137(21), pp. 2958-2969. American Society of Hematology 10.1182/blood.2020010208

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Eosinophils are white blood cells contributing to the regulation of immunity and they are involved in the pathogenesis of numerous inflammatory diseases. In contrast to other cells of the immune system, no information is available about the role of autophagy in eosinophil differentiation and functions. In order to study the autophagic pathway in eosinophils, we generated conditional knockout mice in which Atg5 is deleted within the eosinophil lineage only (designated Atg5eoΔ mice). Eosinophilia was provoked by crossbreeding Atg5eoΔ mice with Il5 (IL-5) overexpressing transgenic mice (designated Atg5eoΔIl5tg mice). Deletion of Atg5 in eosinophils resulted in a dramatic reduction in the number of mature eosinophils in blood and in an increase of immature eosinophils in the bone marrow. Atg5-knockout eosinophil precursors exhibited reduced proliferation under both in vitro and in vivo conditions, but no increased cell death. Moreover, reduced differentiation of eosinophils in the absence of Atg5 was also seen in mouse and human models of chronic eosinophilic leukemia. Atg5-knockout blood eosinophils demonstrated augmented levels of degranulation and bacterial killing in vitro. Moreover, in an experimental in vivo model, we observed that Atg5eoΔ mice achieve better clearance of the local and systemic bacterial infection with Citrobacter (C.) rodentium. Evidence for increased degranulation of ATG5low-expressing human eosinophils was also obtained in both tissues and blood. Taken together, mouse and human eosinophil hematopoiesis and effector functions are regulated by ATG5 which controls the amplitude of overall antibacterial eosinophil immune responses.

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