Adhesion-induced eosinophil cytolysis requires the receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase-like (MLKL) signaling pathway, which is counterregulated by autophagy.

Radonjic-Hoesli, Susanne; Wang, Xiaoliang; de Graauw, Elisabeth Louisa Maria; Stoeckle, Christina; Styp-Rekowska, Beata; Hlushchuk, Ruslan; Simon, Dagmar; Späth, Peter Julius; Yousefi, Shida; Simon, Hans-Uwe (2017). Adhesion-induced eosinophil cytolysis requires the receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase-like (MLKL) signaling pathway, which is counterregulated by autophagy. The Journal of allergy and clinical immunology, 140(6), pp. 1632-1642. Elsevier 10.1016/j.jaci.2017.01.044

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Eosinophils are a subset of granulocytes that can be involved in the pathogenesis of different diseases, including allergy. Their effector functions are closely linked to their cytotoxic granule proteins. Release takes place through several different mechanisms, one of which is cytolysis, which is associated with release of intact granules, so-called clusters of free eosinophil granules. The mechanism underlying this activation-induced form of cell death in eosinophils has remained unclear.


We aimed to elucidate the molecular mechanism of eosinophil cytolysis.


Isolated blood eosinophils were incubated on glass coverslips coated with intravenous immunoglobulin and inactive complement component 3b. A morphologic characterization of the distinct stages of the proposed cascade was addressed by means of time-lapse automated fluorescence microscopy, electron microscopy, and immunohistochemistry. Experiments with pharmacologic inhibitors were performed to elucidate the sequence of events within the cascade. Tissue samples of patients with eosinophilic skin diseases or eosinophilic esophagitis were used for in vivo analyses.


After eosinophil adhesion, we observed reactive oxygen species production, early degranulation, and granule fusion processes, leading to a distinct morphology exhibiting cytoplasmic vacuolization and, finally, cytolysis. Using a pharmacologic approach, we demonstrate the presence of a receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase-like (MLKL) signaling pathway in eosinophils, which, after its activation, leads to the production of high levels of reactive oxygen species in a p38 mitogen-activated protein kinase and phosphatidylinositol 3'-kinase-dependent manner. All these steps are required for cytoplasmic vacuolization and subsequent cytolysis to occur. Interestingly, triggering cytolysis is associated with an induction of autophagy in eosinophils, and additional stimulation of autophagy by means of pharmacologic inhibition of the mechanistic target of rapamycin counterregulates cell death. Moreover, MLKL phosphorylation, cytoplasmic vacuolization, and cytolysis were observed in eosinophils under in vivo inflammatory conditions.


We report that adhesion-induced eosinophil cytolysis takes place through RIPK3-MLKL-dependent necroptosis, which can be counterregulated by autophagy.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Dermatology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Wang, Xiaoliang, de Graauw, Elisabeth Louisa Maria, Simon, Dagmar, Späth, Peter Julius, Yousefi, Shida, Simon, Hans-Uwe


600 Technology > 610 Medicine & health








Jana Berger

Date Deposited:

08 Sep 2017 15:44

Last Modified:

05 Dec 2022 15:05

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Autophagy RIP kinase eosinophil cytolysis eosinophilic disease mixed lineage kinase-like necroptosis necrosis non-apoptotic cell death reactive oxygen species




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