A novel mode of cell death in active versus resting eosinophils: a potential pathway for treatment of asthma and allergic disease

Apoptosis was previously thought to be the only mode of regulated or programmed cell death in eosinophils, as necrosis was regarded as unregulated cell death.  However, Kano et al., have discovered that the activated eosinophils, found in abundance in asthma and allergic disease, can die by means of a type of regulated necrosis in response to Siglec-8 ligation [J Allergy Clin Immunol 2013; 132(2): 437-445]. Siglec-8 is a cell-surface receptor protein that is highly and selectively expressed by human eosinophils, as well as mast cells and basophils. The authors show that Siglec-8 ligation in the presence of IL-5 triggers necrosis in activated eosinophils in a reactive oxygen species (ROS)–dependent manner. Further, they explain why IL-5 promotes cell death in this system even though it is typically a pro-survival signal.  They demonstrate that ROS switch IL-5’s function from pro-survival to cell death enhancement by augmenting ERK phosphorylation and this serves as a decisive trigger of necrotic cell death. These discoveries indicate that necrotic eosinophil cell death can be regulated by signal transduction, suggesting that potential therapeutics targeting regulation of the mode of cell death could be beneficial in various eosinophilic diseases.