Lysophosphatidylserine induces eosinophil extracellular trap formation and degranulation: Implications in severe asthma

Abstract

Background: Recent evidence demonstrates that activated eosinophils undergo a distinct form of lytic cell death, accompanied by formation of DNA-based eosinophil extracellular trap (EET) and degranulation, enhancing inflammatory immune responses in asthmatic airways. We previously showed that human blood eosinophils undergo degranulation in response to lysophosphatidylserine (LysoPS), an inflammatory lipid mediator, and strongly express P2Y10, a LysoPS receptor. Methods: We evaluated EET, degranulation, and cell death of eosinophils in response to various concentrations of LysoPS. We also compared responsiveness to LysoPS between eosinophils from severe and nonsevere asthmatics. Results: Extensive EET formation was elicited from a substantial fraction of stimulated eosinophils in response to 50 μmol/L LysoPS. Analyses for LDH and eosinophil-derived neurotoxin release showed that both lytic cell death and degranulation accompanied EET formation in response to LysoPS. Cytological analyses demonstrated that citrullinated histone 3 was present in the extracellular, filamentous DNA structure embedded with eosinophil granules. The LysoPS-induced EET was independent of ROS production and irrelevant to several signaling pathways examined, but dependent on protein arginine deiminase 4. A low concentration of LysoPS (5 μmol/L) did not induce EET or degranulation, but significantly increased plateletactivating factor-induced degranulation. Eosinophils from severe asthmatics exhibited greater degranulation, but not EET formation, in response to LysoPS (50 μmol/L), than those from nonsevere asthmatics, along with great expression of surface P2Y10. Conclusions: We identified a novel function of LysoPS, namely induction of EET in association with cytolysis and degranulation. LysoPS-dependent EET or degranulation plays a potential role in eosinophilic inflammation of severe asthma.

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

“…Hwang et al demonstrated that lyosphosphatidylserine is capable of inducing eosinophil degranulation via its action on P2Y 10 receptor [ 102 ]. A subsequent study demonstrated the ability of lysophosphatidylserine to induce eosinophil extracellular trap formation [ 117 ]. Because P2Y 10 is highly expressed during late stage eosinophil differentiation and in eosinophils isolated from severe asthmatics, it offers the possibility of targeting eosinophil degranulation without affecting their survival [ 102 , 117 ].…”

“…Human leukocytes were found to differentially express CB 1 and CB 2 receptors as well as MGL [ 251 , 252 , 253 ]. Eosinophils, in particular, were shown to express MGL and CB 2 receptor [ 117 , 251 , 253 ] and were found to migrate towards 2-AG [ 254 , 255 ]. Furthermore, the expression of the CB 2 receptor is increased in eosinophils from symptomatic allergic donors and upregulated following ovalbumin challenge in mice, while CB 1 expression was found to be upregulated in tonsils from allergic rhinitis patients [ 117 , 256 , 257 ].…”

“…Eosinophils, in particular, were shown to express MGL and CB 2 receptor [ 117 , 251 , 253 ] and were found to migrate towards 2-AG [ 254 , 255 ]. Furthermore, the expression of the CB 2 receptor is increased in eosinophils from symptomatic allergic donors and upregulated following ovalbumin challenge in mice, while CB 1 expression was found to be upregulated in tonsils from allergic rhinitis patients [ 117 , 256 , 257 ]. In addition, their endogenous ligand 2-AG was found to be increased following challenge in both a contact dermatitis and dust mite antigen-induced dermatitis mouse model [ 64 , 258 ].…”

Adult‐onset eosinophilic airway diseases

“…14 EETosis is associated with plasma membrane rupture and release of free granules along with histone-retained chromatin structure that is eosinophil extracellular traps (EETs). 9,15,16 EETs are considered an innate immune system to prevent dissemination of pathogens, but their excess formation could be pathogenic. EETs form stable aggregates that contribute to the viscosity of secretions observed in eosinophilic CRS, 15 eosinophilic otitis media 17 and ABPA.…”

“…In inflamed tissue and lumen, eosinophils may undergo an active nonapoptotic cell death termed eosinophil ETosis (EETosis) 14 . EETosis is associated with plasma membrane rupture and release of free granules along with histone‐retained chromatin structure that is eosinophil extracellular traps (EETs) 9,15,16 . EETs are considered an innate immune system to prevent dissemination of pathogens, but their excess formation could be pathogenic.…”