Cyclic GMP-AMP Triggers Asthma in an IL-33-Dependent Manner That Is Blocked by Amlexanox, a TBK1 Inhibitor

Abstract

Extracellular host-derived DNA, as one of damage associated molecular patterns (DAMPs), is associated with allergic type 2 immune responses. Immune recognition of such DNA generates the second messenger cyclic GMP-AMP (cGAMP) and induces type-2 immune responses; however, its role in allergic diseases, such as asthma, has not been fully elucidated. This study aimed to determine whether cGAMP could induce asthma when used as an adjuvant. We intranasally sensitized mice with cGAMP together with house dust mite antigen (HDM), followed by airway challenge with HDM. We then assessed the levels of eosinophils in the broncho-alveolar lavage fluid (BALF) and serum HDM-specific antibodies. cGAMP promoted HDM specific allergic asthma, characterized by significantly increased HDM specific IgG1 and total IgE in the serum and infiltration of eosinophils in the BALF. cGAMP stimulated lung fibroblast cells to produce IL-33 in vitro, and mice deficient for IL-33 or IL-33 receptor (ST2) failed to develop asthma enhancement by cGAMP. Not only Il-33−/− mice, but also Sting−/−, Tbk1−/−, and Irf3−/−Irf7−/− mice which lack the cGAMP-mediated innate immune activation failed to increase eosinophils in the BALF than that from wild type mice. Consistently, intranasal and oral administration of amlexanox, a TBK1 inhibitor, decreased cGAMP-induced lung allergic inflammation. Thus, cGAMP functions as a type 2 adjuvant in the lung and can promote allergic asthma in manners that dependent on the intracellular STING/TBK1/IRF3/7 signaling pathway and the resultant intercellular signaling pathway via IL-33 and ST2 might be a novel therapeutic target for allergic asthma.

Altered transcriptional and chromatin responses to rhinovirus in bronchial epithelial cells from adults with asthma

“…This implies that for half of the transcription factors at regions with decreased accessibility, there is both decreased accessibility of binding sites and decreased availability of transcription factors; for the other half there is increased availability of the corresponding transcription factor despite decreased accessibility of binding sites. Many of the transcription factors with enriched binding motifs at regions with RV-responsive chromatin have been implicated in studies of lung function (FOXP2 25 , EPAS1 26 , SP1 27 ), immune function (IRF1 28 , IRF2 29 , IRF3 30 , BCL6 31 , PRDM1 32 , FOXA3 33 , FOXO1 34 ), and asthma (CTCF 35 , HIF1A 36 , STAT4 37 ).…”

STING activation in alveolar macrophages and group 2 innate lymphoid cells suppresses IL-33–driven type 2 immunopathology

“…To some extent, our current findings on 2′3′-cGAMP are consistent with a new report showing that a bacterial cyclic dinucleotide, c-di-GMP, can effectively inhibit IL-33– or Alternaria -induced type 2 inflammation in mice ( 43 ). However, it has also recently been reported that in another model of allergic inflammation, the administration of 2′3′-cGAMP had an adjuvant effect that exacerbated the HDM-induced Th2 response ( 44 ). This result is contrast to our data presented in Supplemental Figure 7 , in which HDM-induced type 2 inflammation was attenuated by 2′3′-cGAMP administration.…”

Contributions of IL-33 in Non-hematopoietic Lung Cells to Obstructive Lung Disease

“…At baseline, IL-33 and ST2 mRNA and protein expression levels are very low in both human and mouse lung fibroblasts ( 19 , 96 , 97 ). IL-33 expression in lung fibroblasts can be upregulated in vitro by stimulation with TNF-α, TNF superfamily member 14 (also known as LIGHT), IL-1β, and second messenger cyclic GMP-AMP ( 19 , 97 , 98 ) and downregulated by interferon-γ ( 99 ). In vivo , IL-33 expression in lung fibroblasts is increased in mice with bleomycin-induced pulmonary fibrosis ( 56 ), and in patients with idiopathic pulmonary fibrosis ( 100 ).…”