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

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-1 beta production. OVA-induced allergic asthma and associated IL-1 beta production were alleviated in mice with small GTPase Arf6-deficient macrophages. The extracellular ASC specks were slightly engulfed by Arf6(-/- )macrophages, and the IL-1 beta 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.

Automated summary

Asthma exacerbation is triggered by airway macrophages through a prion-like cell-to-cell transmission of extracellular particulates. Mice with small GTPase Arf6-deficient macrophages show alleviated allergic asthma and reduced IL-1 beta production. The Arf6-dependent intercellular transmission of extracellular ASC specks contributes to the amplification of allergic inflammation and subsequent asthma exacerbation.