Arf6 exacerbates allergic asthma through cell-to-cell transmission of ASC inflammasomes
SangJoon Lee, Akari Ishitsuka, Takahiro Kuroki, Yu-Hsien Lin, Akira Shibuya, Tsunaki Hongu, Yuji Funakoshi, Yasunori Kanaho, Kyosuke Nagata, Atsushi Kawaguchi
SangJoon Lee, Akari Ishitsuka, Takahiro Kuroki, Yu-Hsien Lin, Akira Shibuya, Tsunaki Hongu, Yuji Funakoshi, Yasunori Kanaho, Kyosuke Nagata, Atsushi Kawaguchi
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Research Article Inflammation

Arf6 exacerbates allergic asthma through cell-to-cell transmission of ASC inflammasomes

Abstract

Asthma is a chronic inflammatory disease of the airways associated with excess production of Th2 cytokines and lung eosinophil accumulation. This inflammatory response persists in spite of steroid administration that blocks autocrine/paracrine loops of inflammatory cytokines, and the detailed mechanisms underlying asthma exacerbation remain unclear. Here, we show that asthma exacerbation is triggered by airway macrophages through a prion-like cell-to-cell transmission of extracellular particulates, including ASC protein, that assemble inflammasomes and mediate IL-1β production. OVA-induced allergic asthma and associated IL-1β production were alleviated in mice with small GTPase Arf6-deficient macrophages. The extracellular ASC specks were slightly engulfed by Arf6–/– macrophages, and the IL-1β production was reduced in Arf6–/– macrophages compared with that in WT macrophages. Furthermore, pharmacological inhibition of the Arf6 guanine nucleotide exchange factor suppressed asthma-like allergic inflammation in OVA-challenged WT mice. Collectively, the Arf6-dependent intercellular transmission of extracellular ASC specks contributes to the amplification of allergic inflammation and subsequent asthma exacerbation.

Authors

SangJoon Lee, Akari Ishitsuka, Takahiro Kuroki, Yu-Hsien Lin, Akira Shibuya, Tsunaki Hongu, Yuji Funakoshi, Yasunori Kanaho, Kyosuke Nagata, Atsushi Kawaguchi

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Figure 6

SecinH3 suppresses asthma-like allergic inflammation.

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SecinH3 suppresses asthma-like allergic inflammation. (A) Airway macroph...
(A) Airway macrophages obtained from WT mice were treated with 100 μM brefeldin A (BFA), 50 μM SecinH3 (SH3), or 30 μM cytochalasin B (CB). At 3 hours after incubation, cells were further incubated with 1 × 104 particles of purified GFP-ASC specks. The level of secreted IL-1β was examined by ELISA at 6 hours after treatment of purified GFP-ASC specks. ***P < 0.001, 1-way ANOVA with Tukey’s test (mean ± SD from 3 independent experiments). (B–G) OVA-immunized WT mice were intranasally injected with OVA at day 7 after the last immunization. After a 1-day incubation, the mice were intranasally administered with 50 nmol/head SecinH3 and then challenged with OVA at days 10 and 13 after the last immunization. The amount of IL-1β (B), IL-5 (C), IL-13 (D), and OVA-specific IgE (E) and the number of Siglec-F–positive granulocytes (F) in BALF were examined at day 1 after the last OVA challenge by ELISA and FACS, respectively (n = 5–10 mice per group). Each symbol represents 1 mouse. ***P < 0.001, 2-tailed Student’s t test. The combined results from 2 independent experiments are shown. Lung tissue sections were stained with PAS-hematoxylin at day 1 after the last OVA challenge (G). Scale bar: 150 μm (top); 20 μm (bottom). Data are representative of 3 independent experiments.