Cytoskeletal and microtubule machineries in concert with integrins are required for the secretion of eosinophil-associated RNases (110.13)

Abstract

Abstract Eosinophils, both as end-stage effector cells and as collaborative interacting components of innate immune responses, have the capacity to secrete varied cytotoxic proteins that are stored in their cytoplasmic secretory granules, termed specific granules. Among them are the eosinophil-associated RNases (EARs): the human eosinophil-derived neurotoxin and eosinophilic cationic protein. The mouse EAR family includes at least 13 members, six of which were found to be present in specific granules. In the last decade several studies, both in vitro and in vivo, have revealed a role for eosinophils and their EARs in anti-viral defense. However, the secretion mechanism of EARs is not fully understood, especially in mouse eosinophils. Therefore, our study aimed to understand the mechanism of EAR secretion following physiological stimulation with chemokines. We found that dynamic polymerization of the actin cytoskeleton and microtubules, as well as functional integrins were critical for CCR3-mediated secretion of EARs. However, inhibition of regulatory components of the cytoskeletal machinery, such as Rac1 and ROCK-I and -II, increased EARs secretion in mouse and human eosinophils, suggesting a negative regulation of these effectors on EARs secretion. Collectively, these data suggest a mechanism by which EARs are secreted from eosinophils under physiological stimulation, findings that are pertinent to host defense against RNA viruses and eosinophil-associated diseases.