Regulation of eosinophil functions by autophagy

Abstract

Eosinophils are granule-containing leukocytes which develop in the bone marrow. For many years, eosinophils have been recognized as cytotoxic effector cells, but recent studies suggest that they perform additional immunomodulatory and homeostatic functions. Autophagy is a conserved intracellular process which preserves cellular homeostasis. Autophagy defects have been linked to the pathogenesis of many human disorders. Evidence for abnormal regulation of autophagy, including decreased or increased expression of autophagy-related (ATG) proteins, has been reported in several eosinophilic inflammatory disorders, such as Crohn's disease, bronchial asthma, eosinophilic esophagitis, and chronic rhinosinusitis. Despite the increasing extent of research using preclinical models of immune cell-specific autophagy deficiency, the physiological relevance of autophagic pathway in eosinophils has remained unknown until recently. Owing to the increasing evidence that eosinophils play a role in keeping organismal homeostasis, the regulation of eosinophil functions is of considerable interest. Here, we discuss the most recent advances on the role of autophagy in eosinophils, placing particular emphasis on insights obtained in mouse models of infections and malignant diseases in which autophagy has genetically dismantled in the eosinophil lineage. These studies pointed to the possibility that autophagy-deficient eosinophils exaggerate inflammation. Therefore, the pharmacological modulation of the autophagic pathway in these cells could be used for therapeutic interventions.

Keywords: Autophagy; Degranulation; Differentiation; Eosinophil; Eosinophilic disease; Eosinophilic leukemia.

Fig. 1

Schematic representation of the mammalian autophagy pathway. a Upon initiation of autophagy, a small portion of the cytoplasm is enclosed by the phagophore (also known as isolation membrane) which may originate from an ER-based structure. Elongation of the phagophore is followed by the autophagosome completion and its fusion with the lysosome, where the engulfed contents are degraded within the autolysosome. b ULK and class III PI3K (VPS34) protein complexes are required for the phagophore initiation. In addition, ATG12 and LC3 ubiquitin-like conjugation systems are necessary for subsequent elongation of the phagophore and its closure. c Autophagy is largely regulated by the activity of mTORC1, which reflects cellular nutritional status. Sufficient amounts of amino acids and growth factors suppress autophagy due to the inactivation of ULK complex by mTORC1 activity. On the contrary, mTORC1 activity is inhibited by cellular stress such as energy deprivation, DNA damage, and hypoxia, leading to the release and activation of the ULK complex which initiates the formation of autophagosomes

Fig. 2.

The role of ATG5 in eosinophil differentiation and effector functions. Atg5-knockout eosinophil precursors with suppressed autophagy exhibit a delayed and reduced proliferation, maturation, p38 and p44/42 MAPK activation, and a reduced expression of Gata-1, C/ebpε, Pu.1, and Trib1 transcription factors (TFs). A decrease in eosinophil differentiation results in reduced numbers of mature eosinophils in blood and peripheral tissues. The differentiation capacity of eosinophil precursors in the absence of Atg5/ATG5 is reduced in established mouse (FIP1L1-PDGFRα; F/P mice) and human eosinophil leukemia models (EoL-1 cells). Moreover, Atg5-knockout eosinophils exhibit enhanced degranulation, EET formation, bacterial killing, and signaling transduction following their activation in vitro. Mice with Atg5-knockout eosinophils have been shown to better clear a bacterial infection with C. rodentium. ATG5^low-expressing human eosinophils demonstrate enhanced degranulation abilities in both tissues and blood