Bronchial asthma is a common, chronic and inflammatory disease with increasing prevalence, affecting over 300 millions people [1]. Dysfunction of the epithelium, persistent airway inflammation, and airway remodeling are the core processes of asthma. Airway epithelium expresses pattern recognition receptors (PRRS) to quickly respond to pathogen-related molecular patterns (PAMPS) and damage-related molecular patterns (DAMPS) and finally mediates inflammatory and immunity reaction by synthesizing and secreting inflammatory mediators [2], [3], [4]. Study has showed that stimulation by HDM allergen, one of the most common allergens and up to 85 % of patients with asthma are allergic to it [5], disrupted the function of epithelial cells and promoted airway inflammation [6], [7]. Cutting off the inflammatory response of epithelial cells could be a potential target for biological therapy of asthma.

Asthma attacks are usually accompanied by significant airway inflammation. Pyroptosis is an inflammatory programmed cell death [8], [9], [10]. During the pyroptosis process, stimuli like lipopolysaccharide (LPS) results in activation of cleaved Gasdermin D (GSDMD) which as a pore-forming effector leading to cytolysis and release of inflammatory factors such as interleukin-1β (IL-1β) [11], [12]. Study has showed that expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and cysteinyl aspartate specific proteinase 1 (Caspase-1) in bronchoalveolar lavage fluid of asthmatic patients were significantly higher than healthy individuals and similar results have been found in murine house dust mites (HDM)/Ovalbumin (OVA) models [13]. A study in vivo found the up-regulated of NLRP3 and Caspase-1in airway epithelial cells resulting in increased levels of IL-1β and tumor necrosis factor (TNF)-α [14]. Further, pyroptosis is also involved in extra-pulmonary immune inflammatory diseases, such as inflammatory bowel disease [15]. Our previous study found that pyroptosis may occur in airway epithelial cells through activation of NLRP3 and GSDMD splicing, thereby increasing airway inflammation and hyperresponsiveness [16]. Taken together, studies suggest that pyroptosis in airway epithelial cells are an initiation for inflammation of asthma. However, a comprehensive dissection of airway epithelial cells pyroptosis in HDM induced asthma is lacking.

In pathological situations, DNA damage can lead to the accumulation of cytoplasmic DNA [17]. Cytoplasmic DNA as a potential danger signal, leads to activation of the innate immune response, with the release of type I interferon (IFN) and IL-1β, marked inflammatory factor of pyroptosis [17], [18], [19]. In this process, cyclic guanylate adenylate synthase (cGAS) induces the production of cGAMP, and combines interferon gene stimulator (STING) which activates tank binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3), and finally leads to the transcription of IFN and other cytokines [18], [20], [21]. In murine OVA and HDM-induced asthma models, the accumulation of double-stranded DNA (dsDNA) in airway epithelial cells is increased, while knockdown of cGAS significantly improves inflammation, mucus secretion, and airway hyperresponsiveness [22]. Another study found that rhinovirus infection can induce the release of dsDNA, promoting type 2 immune response [23]. Those researches suggest dsDNA-cGAS-STING pathway may be participate in asthma occurrence. In retinal pigment epithelial cells, the mitochondrial DNA interacts with cGAS and activates inflammasome and GSDMD [24]. On the other hand, Banerjee et al. reported that GSDMD inhibits the response of cGAS [25]. However, the underlying mechanism between cGAS-STING pathway and pyroptosis is still unclear in asthma.

HSP90 is an important molecular chaperone, participating in many physiological and pathological processes including DNA damage, innate immunity and pyroptosis [26], [27], [28]. It has been reported HSP90 closely related to the occurrence and development of asthma [29], [30], [31]. HSP90 has α and β two major subtypes [26], and former regulates cell function, while the latter participates in cell survival [9]. We previously confirmed that inhibition of HSP90α rescued dysfunction of airway epithelial cells in HDM-induced asthma models [7], but it is unknown whether HSP90α is involved in cGAS-STING pathway and pyroptosis in asthma.

In the study we finds that treating with HSP90 inhibitor 17-AAG could improve airway inflammation while inhibiting pyroptosis induced by HDM. Meanwhile, the DNA-cGAS-STING pathway was also inhibited in vitro. Further analysis shows that up-regulation of HSP90α increases cross-linking between STING and endoplasmic reticulum (ER), finally causing pyroptosis. As a detectable indicator in serum, HSP90α may be a promising target in asthma therapy.