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Extracellular histones aggravate inflammation in ARDS by promoting alveolar macrophage pyroptosis
Ping Jiang1, Yang Jin2, Meng Sun2
1Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, PR China.
Abstract:
Extracellular histones have been discovered to play a pathogenic role in ARDS, but the underlying mechanisms are yet to be fully defined. Alveolar macrophage (AM) is essential for the initiation and progression of lung inflammation; of note, AM pyroptosis has been suggested contributing to ARDS-associated inflammation. Here we aimed to investigate whether extracellular histones promote ARDS by triggering AM pyroptosis. The BALF samples of ARDS patients were collected and AMs were further isolated. Extracellular histones, AM pyroptosis, and pyroptosis-associated mediators were measured. Furthermore, the effects of extracellular histones on AM pyroptosis and the underlying mechanisms were investigated. It showed that extracellular histones were markedly elevated in the BALF of ARDS patients and correlated with the increased AM pyroptosis. ARDS patient's BALF induced pronounced pyroptosis in cultured human monocytes, which could be prevented by neutralizing extracellular histones with heparin. In addition, exogenous histones induced pyroptosis of MH-S cells in a dose- and time-dependent manner, which acted through the NLRP3 inflammasome signaling pathway. Inhibition of NLRP3 inflammasome signaling substantially reduced cell pyroptosis. In a murine model of LPS-induced ARDS, extracellular histones were increased in the BALF and its increase was associated with enhanced AM pyroptosis and exaggerated lung inflammation. Blockade of extracellular histones or NLPR3 inflammasome equally inhibited macrophage pyroptosis, whereas targeting histones appeared more effective in alleviating lung inflammation. This study suggested that extracellular histones promote AM pyroptosis through NLRP3 inflammasome pathway, which in turn aggravates lung inflammation in ARDS. Pharmacological manipulation of extracellular histones or AM pyroptosis may become promising strategies for the treatment of ARDS.
Insights
Extracellular histones trigger alveolar macrophage pyroptosis via the NLRP3 inflammasome pathway, worsening acute respiratory distress syndrome (ARDS) lung inflammation. Targeting histones may offer effective ARDS treatment.
Area of Science:
- Immunology
- Pulmonology
- Cell Biology
Background:
- Extracellular histones are implicated in acute respiratory distress syndrome (ARDS) pathogenesis.
- Alveolar macrophages (AMs) drive lung inflammation in ARDS, with AM pyroptosis a suspected contributor.
- The precise mechanisms linking extracellular histones to AM pyroptosis in ARDS require elucidation.
Purpose of the Study:
- To investigate if extracellular histones promote ARDS by inducing AM pyroptosis.
- To explore the underlying molecular pathways involved in histone-mediated AM pyroptosis.
- To assess the therapeutic potential of targeting extracellular histones or AM pyroptosis in ARDS.
Main Methods:
- Analysis of bronchoalveolar lavage fluid (BALF) from ARDS patients and healthy controls.
- Isolation and culture of alveolar macrophages (AMs) and human monocytes.
- Measurement of extracellular histones, AM pyroptosis markers, and inflammatory mediators.
- In vitro experiments using exogenous histones and cell lines (MH-S).
- In vivo studies using a murine model of LPS-induced ARDS.
- Pharmacological inhibition of NLRP3 inflammasome and extracellular histones.
Main Results:
- Extracellular histones were significantly elevated in ARDS BALF and correlated with increased AM pyroptosis.
- ARDS BALF induced pyroptosis in human monocytes, preventable by heparin (histone neutralization).
- Exogenous histones induced dose- and time-dependent pyroptosis in MH-S cells via the NLRP3 inflammasome pathway.
- Inhibition of NLRP3 inflammasome reduced histone-induced pyroptosis.
- In a murine ARDS model, elevated extracellular histones correlated with enhanced AM pyroptosis and lung inflammation.
- Blocking extracellular histones or NLRP3 inflammasome inhibited macrophage pyroptosis, but targeting histones was more effective in reducing lung inflammation.
Conclusions:
- Extracellular histones promote AM pyroptosis through the NLRP3 inflammasome pathway, exacerbating lung inflammation in ARDS.
- Targeting extracellular histones shows promise as a therapeutic strategy for ARDS.
- Modulating AM pyroptosis represents another potential avenue for ARDS treatment.
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