STING agonist diABZI induces PANoptosis and DNA mediated acute respiratory distress syndrome (ARDS)

Stimulator of interferon genes (STING) contributes to immune responses against tumors and may control viral infection including SARS-CoV-2 infection. However, activation of the STING pathway by airway silica or smoke exposure leads to cell death, self-dsDNA release, and STING/type I IFN dependent acute lung inflammation/ARDS. The inflammatory response induced by a synthetic non-nucleotide-based diABZI STING agonist, in comparison to the natural cyclic dinucleotide cGAMP, is unknown. A low dose of diABZI (1 mu g by endotracheal route for 3 consecutive days) triggered an acute neutrophilic inflammation, disruption of the respiratory barrier, DNA release with NET formation, PANoptosis cell death, and inflammatory cytokines with type I IFN dependent acute lung inflammation. Downstream upregulation of DNA sensors including cGAS, DDX41, IFI204, as well as NLRP3 and AIM2 inflammasomes, suggested a secondary inflammatory response to dsDNA as a danger signal. DNase I treatment, inhibition of NET formation together with an investigation in gene-deficient mice highlighted extracellular DNA and TLR9, but not cGAS, as central to diABZI-induced neutrophilic response. Therefore, activation of acute cell death with DNA release may lead to ARDS which may be modeled by diABZI. These results show that airway targeting by STING activator as a therapeutic strategy for infection may enhance lung inflammation with severe ARDS.

Automated summary

Stimulator of interferon genes (STING) plays an important role in immune responses against tumors and viral infections. However, activation of the STING pathway by airway silica or smoke exposure can lead to cell death and lung inflammation. The inflammatory response induced by a synthetic STING agonist called diABZI, compared to a natural cyclic dinucleotide cGAMP, is not well understood. This study found that diABZI caused acute neutrophilic inflammation, disrupted the respiratory barrier, released DNA with formation of neutrophil extracellular traps (NETs), and triggered cell death and inflammatory cytokines associated with lung inflammation. These results suggest that using STING activators as therapeutic strategies for infections may worsen lung inflammation and lead to severe acute respiratory distress syndrome (ARDS).