BACKGROUND & AIMS: Acute pancreatitis (AP) frequently progresses to systemic inflammation and acute lung injury, but the circulating mediators that couple pancreatic inflammation to remote organ damage remain poorly characterized. Following our finding that plasma exosomes induce AP-associated lung injury by triggering NOD-like receptor protein 3 (NLRP3)-dependent pyroptotic death in alveolar macrophages (AMs), this study aims to identify exosome-encapsulated S100A8/A9 derived from Kupffer cells (KCs) as a critical propagator of this inflammatory cascade. METHODS: Levels of S100A8/A9 in plasma-derived exosomes from AP mice were quantified and correlated with pulmonary cytokine profiles. Plasma exosomes were characterized and administered to AMs and healthy mice, followed by evaluation of their capacity to induce pyroptosis and lung injury. The specific role of S100A8/A9 was tested using genetic knockout and/or pharmacological inhibition. Furthermore, KCs were investigated as a putative cellular source of these exosomes by utilizing a combination of in vitro stimulation and in vivo depletion models. Finally, the role of S100A8/A9 in perturbing the lysosomal pathway was mechanistically dissected to reveal the pathway underlying NLRP3 inflammasome activation and pyroptosis. RESULTS: Elevated plasma S100A8/A9 levels paralleled pulmonary cytokines increases in AP mice, and the circulating S100A8/A9 was predominantly carried by exosomes. Rapidly internalized by alveolar macrophages, AP exosomes delivered S100A8/A9 to induce pyroptosis. Adoptive transfer of AP-derived exosomes into healthy mice reproduced lung injury, whereas exosomes lacking S100A9 or from KCs-depleted AP mice caused markedly less pathological alterations. Mechanistically, exosomal S100A8/A9 activated the NLRP3 inflammasome and executed pyroptosis through a pathway via suppression of heat shock protein 70-dependent acid sphingomyelinase, leading to sphingomyelin accumulation and lysosomal membrane permeabilization. CONCLUSIONS: These findings uncover a pancreas-liver-lung inflammatory axis in which KCs-derived exosomal S100A8/A9 drives systemic inflammation in AP, representing a tractable therapeutic target to prevent extrapancreatic organ injury.
He et al. (Fri,) studied this question.