| RRC ID |
68101
|
| Author |
Lee S, Ishitsuka A, Kuroki T, Lin YH, Shibuya A, Hongu T, Funakoshi Y, Kanaho Y, Nagata K, Kawaguchi A.
|
| Title |
Arf6 exacerbates allergic asthma through cell-to-cell transmission of ASC inflammasomes.
|
| Journal |
JCI Insight
|
| 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.
|
| Volume |
6(16)
|
| Published |
2021-8-23
|
| DOI |
10.1172/jci.insight.139190
|
| PII |
e139190
|
| PMID |
34423792
|
| PMC |
PMC8410019
|
| MeSH |
ADP-Ribosylation Factor 6 / antagonists & inhibitors
ADP-Ribosylation Factor 6 / genetics
ADP-Ribosylation Factor 6 / metabolism*
Animals
Asthma / drug therapy
Asthma / immunology*
Asthma / pathology
CARD Signaling Adaptor Proteins / metabolism
Cell Communication / drug effects
Cell Communication / immunology*
Disease Models, Animal
Humans
Inflammasomes / drug effects
Inflammasomes / immunology*
Inflammasomes / metabolism
Interleukin-1beta / metabolism
Lung / immunology
Lung / pathology
Macrophages, Alveolar / immunology*
Macrophages, Alveolar / metabolism
Mice
Mice, Knockout
Ovalbumin / administration & dosage
Ovalbumin / immunology
Phagocytosis / drug effects
Symptom Flare Up
THP-1 Cells
Th2 Cells
Triazoles / administration & dosage
|
| IF |
6.205
|
| Resource |
| Human and Animal Cells |
THP-1(RCB1189) |
