AI Article Synopsis

  • Severe acute pancreatitis (SAP) leads to increased macrophage activation and pyroptosis, contributing to immune suppression and lung injury, with cGAS-STING playing a critical role in these processes.* -
  • Experiments using wild type and genetically modified mice, along with in vitro cell tests, demonstrate that disrupting cGAS/STING pathways can reduce inflammasome activation and macrophage death, lessening lung injury related to SAP.* -
  • The study suggests that targeting components of the mtDNA-cGAS-STING pathway could provide therapeutic strategies to mitigate the harmful immune responses associated with SAP-induced lung injury.*

Article Abstract

Background: Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS-STING in SAP-induced lung injury (LI) remains unknown.

Methods: Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS and sting mice. Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro.

Results: SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS/STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA-cGAS-STING axis and the NLRP3-pyroptosis axis.

Conclusions: Negative regulation of any molecule in the mtDNA-cGAS-STING-IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11055249PMC
http://dx.doi.org/10.1186/s11658-024-00575-9DOI Listing

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