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.
Highlights
Asthma is a common chronic respiratory illness with an increasing prevalence especially in developed countries [1, 2]
When we examined the numbers of total cells, eosinophils, alveolar macrophages, neutrophil, B cells, and T cells in broncho-alveolar lavage fluid (BALF), significantly higher numbers were observed in the mice sensitized with house dust mite antigen (HDM) + cyclic GMP-AMP (cGAMP) than in the control mice (Figure 2D)
We previously reported that cGAMP and other stimulator of interferon (IFN) genes (STING) ligands function as type 2 adjuvants, characterized by the induction of serum IgE levels, suggesting that cGAMP may be one of the endogenous factors for the promotion of type 2 immune responses and allergic asthma
Summary
Asthma is a common chronic respiratory illness with an increasing prevalence especially in developed countries [1, 2]. Asthma may consist of many phenotypes based on the onset of disease [3, 4]. Of these phenotypes, early-onset asthma during childhood is mainly associated with type 2 immune responses. Early-onset asthma during childhood is mainly associated with type 2 immune responses Many factors, such as infection, environmental factors, and genetic factors, contribute to the onset of asthma [5], the mechanism by which type 2 immune responses are activated remains elusive. Other work demonstrated that host-derived DNA is recognized as a damage-associated molecular pattern (DAMP) and induces type 2 immune responses and allergic inflammation [7]. The mechanisms responsible for the recognition of this DNA and the subsequent induction of immune responses are not fully understood
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