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Over 20 million Americans are affected by allergies such as asthma and allergic rhinitis, which can be caused by common allergens like house dust mites (HDM) or their associated components. The exacerbation of allergies can be fatal in patients with pre-existing chronic lung inflammation. Until now, there is no cure for asthma and type 2 allergies and the only available treatments aim to reduce the disease symptoms. Thus, there is an urgent need to understand the pathogenic mechanism of HDM-induced allergic responses. Since HDM play a major role in triggering allergic reactions, several studies focused on identifying their constituents. Although it is important to study HDM protein components that elicit adaptive type 2 inflammation (e.g. Der p 1), the role of innate sensors such as Toll-like receptors (TLRs) is unknown. A number of studies investigated presence of common adjuvants that may activate host immune receptors and modulate allergic diseases, for example, lipopolysaccharide (LPS) contaminating HDM triggered asthma in mice through acting on TLR4. In addition, single and double-stranded nucleic acids from bacteria or viruses can also act as adjuvants that stimulate innate immune receptors. Clearly, diverse allergen-associated components play an essential role in modulating type 2 lung inflammation in allergic patients. Recently, we have shown that HDM contain immunogenic RNA capable of modulating type 2 lung inflammation by inducing protective interferon responses. Using RNA-seq analysis, we show that HDM contain previously uncharacterized double stranded RNA sequences derived from novel RNA-viruses. Our findings suggest that other allergens may also have immunostimulatory RNA that can regulate type 2 lung inflammation.

2'3'-cGAMP is known as a nonclassical second messenger and small immune modulator that possesses potent antitumor and antiviral activities via inducing the stimulator of IFN genes-mediated (STING-mediated) signaling pathway. However, its function in regulating type 2 immune responses remains unknown. Therefore, we sought to determine a role of STING activation by 2'3'-cGAMP in type 2 inflammatory reactions in multiple mouse models of eosinophilic asthma. We discovered that 2'3'-cGAMP administration strongly attenuated type 2 lung immunopathology and airway hyperreactivity induced by IL-33 and a fungal allergen, Aspergillus flavus. Mechanistically, upon the respiratory delivery, 2'3'-cGAMP was mainly internalized by alveolar macrophages, in which it activated the STING/IFN regulatory factor 3/type I IFN signaling axis to induce the production of inhibitory factors containing IFN-α, which blocked the IL-33-mediated activation of group 2 innate lymphoid (ILC2) cells in vivo. We further demonstrated that 2'3'-cGAMP directly suppressed the proliferation and function of both human and mouse ILC2 cells in vitro. Taken together, our findings suggest that STING activation by 2'3'-cGAMP in alveolar macrophages and ILC2 cells can negatively regulate type 2 immune responses, implying that the respiratory delivery of 2'3'-cGAMP might be further developed as an alternative strategy for treating type 2 immunopathologic diseases such as eosinophilic asthma.