RESUMEN
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-1ß production. OVA-induced allergic asthma and associated IL-1ß production were alleviated in mice with small GTPase Arf6-deficient macrophages. The extracellular ASC specks were slightly engulfed by Arf6-/- macrophages, and the IL-1ß 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.
Asunto(s)
Factor 6 de Ribosilación del ADP/metabolismo , Asma/inmunología , Comunicación Celular/inmunología , Inflamasomas/inmunología , Macrófagos Alveolares/inmunología , Factor 6 de Ribosilación del ADP/antagonistas & inhibidores , Factor 6 de Ribosilación del ADP/genética , Animales , Asma/tratamiento farmacológico , Asma/patología , Proteínas Adaptadoras de Señalización CARD/metabolismo , Comunicación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Inflamasomas/efectos de los fármacos , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Pulmón/inmunología , Pulmón/patología , Macrófagos Alveolares/metabolismo , Ratones , Ratones Noqueados , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Fagocitosis/efectos de los fármacos , Brote de los Síntomas , Células THP-1 , Células Th2 , Triazoles/administración & dosificaciónRESUMEN
The respiratory epithelium is exposed to the environment and initiates inflammatory responses to exclude pathogens. Influenza A virus (IAV) infection triggers inflammatory responses in the respiratory mucosa, but the mechanisms of inflammasome activation are poorly understood. We identified MxA as a functional inflammasome sensor in respiratory epithelial cells that recognizes IAV nucleoprotein and triggers the formation of ASC (apoptosis-associated speck-like protein containing a CARD) specks via interaction of its GTPase domain with the PYD domain of ASC. ASC specks were present in bronchiolar epithelial cells of IAV-infected MxA-transgenic mice, which correlated with early IL-1ß production and early recruitment of granulocytes in the lungs of infected mice. Collectively, these results demonstrate that MxA contributes to IAV resistance by triggering a rapid inflammatory response in infected respiratory epithelial cells.
