Exophilin-5 regulates allergic airway inflammation by controlling IL-33–mediated Th2 responses
Katsuhide Okunishi, … , Susumu Nakae, Tetsuro Izumi
Katsuhide Okunishi, … , Susumu Nakae, Tetsuro Izumi
Published April 2, 2020
Citation Information: J Clin Invest. 2020;130(7):3919-3935. https://doi.org/10.1172/JCI127839.
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Research Article Immunology

Exophilin-5 regulates allergic airway inflammation by controlling IL-33–mediated Th2 responses

Abstract

A common variant in the RAB27A gene in adults was recently found to be associated with the fractional exhaled nitric oxide level, a marker of eosinophilic airway inflammation. The small GTPase Rab27 is known to regulate intracellular vesicle traffic, although its role in allergic responses is unclear. We demonstrated that exophilin-5, a Rab27-binding protein, was predominantly expressed in both of the major IL-33 producers, lung epithelial cells, and the specialized IL-5 and IL-13 producers in the CD44hiCD62LloCXCR3lo pathogenic Th2 cell population in mice. Exophilin-5 deficiency increased stimulant-dependent damage and IL-33 secretion by lung epithelial cells. Moreover, it enhanced IL-5 and IL-13 production in response to TCR and IL-33 stimulation from a specific subset of pathogenic Th2 cells that expresses a high level of IL-33 receptor, which exacerbated allergic airway inflammation in a mouse model of asthma. Mechanistically, exophilin-5 regulates extracellular superoxide release, intracellular ROS production, and phosphoinositide 3-kinase activity by controlling intracellular trafficking of Nox2-containing vesicles, which seems to prevent the overactivation of pathogenic Th2 cells mediated by IL-33. This is the first report to our knowledge to establish the significance of the Rab27-related protein exophilin-5 in the development of allergic airway inflammation, and provides insights into the pathophysiology of asthma.

Authors

Katsuhide Okunishi, Hao Wang, Maho Suzukawa, Ray Ishizaki, Eri Kobayashi, Miho Kihara, Takaya Abe, Jun-ichi Miyazaki, Masafumi Horie, Akira Saito, Hirohisa Saito, Susumu Nakae, Tetsuro Izumi

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Figure 10

NAPDH oxidase inhibitor DPI significantly suppresses phenotypes in CD4+ T cells induced by exophilin-5 deficiency.

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NAPDH oxidase inhibitor DPI significantly suppresses phenotypes in CD4+ ...
After a 10-minute preincubation with and without DPI (160 nM), cells were plated into anti-CD3ε Ab–coated wells to examine the effect of DPI on IL-33R expression (A) and on production of IL-5 and IL-13 (B and C). (A) Effect of DPI on IL-33R expression. After a 10-minute preincubation with and without DPI and 2.5 hours of culture in the presence of anti-CD3ε Ab (CD3), cell surface IL-33R levels were determined. *P < 0.05 by paired t test. Tpath2, pathogenic Th2 cells. (B and C) Effects of DPI on IL-33–mediated IL-5 production under TCR stimulation by CD4+ T cells obtained from OVA-sensitized WT and Exph5-KO mice (B), or on IL-33–mediated IL-5 and IL-13 production by CD4+ T cells from OVA-sensitized BM-chimeric mice (C). IL-5 levels in the supernatants after 2-day culture were determined by ELISA as described in Figure 8, C and D. Data were obtained from n = 4–6 mice from 2 to 4 independent experiments. ##P < 0.01; ###P < 0.001 by 1-way ANOVA with Tukey’s post hoc test. (D) Scheme for exophilin-5 regulation of pathogenic Th2 cell functions. See text in Discussion.