Uncovering the secretes of allergic inflammation
Michael Brusilovsky, Mark Rochman, Nurit P. Azouz, Lydia E. Mack, Marc E. Rothenberg
Michael Brusilovsky, Mark Rochman, Nurit P. Azouz, Lydia E. Mack, Marc E. Rothenberg
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Commentary

Uncovering the secretes of allergic inflammation

Abstract

Allergic asthma is a chronic inflammatory lung disease associated with increased cytokine secretion. Aspects of airway inflammation are also linked to a common genetic variant that corresponds to the small GTPase, Rab27, a protein involved in vesicular trafficking in immune cells. However, the mechanisms by which Rab27 contributes to airway inflammation and cytokine release remain ambiguous. In this issue of the JCI, Okunishi et al. explored the role that the Rab27 effector, exophilin-5, has in allergic inflammation. Exophilin-5–deficient mice and asthma mouse models revealed that exophilin-5 regulates IL-33 production and the Th2 response. Notably, exophilin-5 deletion enhanced IL-33 release and pathogenic Th2 responsiveness through the mTOR pathway and altered intracellular IL-33 trafficking. This work provides insights into the molecular mechanisms that underlie inflammatory lung disease.

Authors

Michael Brusilovsky, Mark Rochman, Nurit P. Azouz, Lydia E. Mack, Marc E. Rothenberg

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Figure 1

Model for exophilin-5 regulation of cellular traffic and secretion mechanisms and type 2 allergic immunity.

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Model for exophilin-5 regulation of cellular traffic and secretion mecha...
Exophilin-5 has a central regulatory role in controlling the cellular traffic of vesicles, as well as impairing protein transport and recycling and IL-33 production. Exophilin-5 deficiency terminates vesicular trafficking mechanisms and disrupts protein recycling, autophagy, and secretion. Exophilin-5 deficiency also enhances mTOR/PIK3 signaling and ROS production. These intrinsic processes result in IL-33 accumulation and enhanced lung epithelial cell fragility, respectively, followed by IL-33 release from damaged cells. Enhanced ST2 expression in exophilin-5–deficient effector T cells and eosinophils induces proatopic cytokine release and immune cell cytotoxicity and degranulation. Taken together, these processes lead to exaggerated type 2 immunity.