Abscisic acid for acute respiratory distress syndrome therapy by suppressing alveolar macrophage pyroptosis via upregulating acyloxyacyl hydrolase expression

Abscisic acid (ABA) is a phytohormone that inhibits airway inflammation in acute respiratory distress syndrome (ARDS) mouse models. However, the molecular mechanism underlying this phenomenon remains unclear. Methods: Serum ABA level in patients and mice was measured via liquid chromatography–tandem mass spectrometry (LC–MS/MS). In-depth molecular mechanism was investigated through transmission electron microscopy, RNA-sequencing, and molecular docking in ARDS mice and cultured primary alveolar macrophages (AMs). We found that the serum ABA level was remarkably decreased in ARDS mice and patients. ABA inhibited lipopolysaccharide (LPS)-induced airway inflammation in mice; moreover, it downregulated genes associated with pyroptosis, as shown by RNA-sequencing and lung protein immunoblots. ABA inhibited the formation of membrane pores in AMs and suppressed the cleavage of gasdermin D (GSDMD) and the activation of caspase-11 and caspase-1 in vivo and in vitro; however, the overexpression of caspase-11 reversed the protective effect of ABA on LPS-induced pyroptosis of primary AMs. ABA inhibited intra-AM LPS accumulation while increasing the level of acyloxyacyl hydrolase (AOAH) in AMs, whereas AOAH deficiency abrogated the suppressive action of ABA on inflammation, pyroptosis, and intra-AM LPS accumulation in vivo and in vitro. Importantly, ABA promoted its intracellular receptor lanthionine C-like receptor 2 interacting with transcription factor peroxisome proliferator-activated receptor γ, which ultimately leading to increase AOAH expression to inactivate LPS and inhibit pyroptosis in AMs. ABA protected against LPS-induced lung injury by inhibiting pyroptosis in AMs via proliferator-activated receptor γ-mediated AOAH expression. Mechanism scheme. ABA promotes the formation of a complex of LANCL2 and PPARγ and increases AOAH expression for cytosolic LPS inactivation, which ultimately leading to inhibition of alveolar macrophages pyroptosis. Black arrows: the classical pathway that had been studied previously. Red arrows: the new GSDMD signal pathway of ABA suppressing ARDS that we discovered in our study. [Display omitted]