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 1

Asthma exacerbation is alleviated in macrophage-Arf6 cKO mice.

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Asthma exacerbation is alleviated in macrophage-Arf6 cKO mice. WT and ma...
WT and macrophage-Arf6 cKO mice were immunized by intraperitoneal injection of OVA with aluminium hydroxide as an adjuvant once per week for 3 weeks. At days 7, 10, and 13 after the last immunization, the mice received intranasal injection of OVA. (A) At day 1 after the last OVA challenge, the number of each indicated leukocyte subset in BALF obtained from WT and macrophage-Arf6 cKO (Arf6 cKO) mice was examined by FACS (n = 3 mice per group; mean ± SD are shown). ***P < 0.001, 1-way ANOVA with Tukey’s test for CD45.2-positive cells. (B) The number of Siglec-F–positive granulocytes in BALF obtained from WT and macrophage-Arf6 cKO mice was examined by FACS (n = 5 mice per group). The combined results from 2 independent experiments are shown. ***P < 0.001; 1-way ANOVA with Tukey’s test. (C) Lung tissue sections were stained with PAS-hematoxylin at day 1 after the last OVA challenge. Data are representative of 3 independent experiments. Scale bar: 150 μm (top); 20 μm (bottom). (D) The number of Siglec-F–positive granulocytes in BALF obtained from WT and macrophage-Arf6 cKO mice challenged with HDM was examined by FACS (n = 5 mice per group). ***P < 0.001, 2-tailed Student’s t test. (E–H) The amount of OVA-specific IgG1 in serum (E), OVA-specific IgE in BALF (F), IL-5 in BALF (G), and IL-13 in BALF (H) obtained from the indicated mice was examined by ELISA (n = 5–14 mice per group). Each symbol represents 1 mouse. The combined results from 2 independent experiments are shown. ***P < 0.001, 2-tailed Student’s t test.