LBH589 reduces oxidized mitochondrial DNA and suppresses NLRP3 inflammasome activation to relieve pulmonary...

Area of Science:

• Immunology
• Pharmacology
• Cell Biology

Background:

• The NLRP3 inflammasome is crucial in ARDS pathogenesis, mediating inflammation via caspase-1 activation and pyroptosis.
• LBH589, a pan-histone deacetylase inhibitor, shows anti-inflammatory potential, but its role in ARDS is unestablished.
• Understanding LBH589's mechanism against NLRP3 inflammasome activation is vital for ARDS therapeutic development.

Purpose of the Study:

• To investigate the inhibitory effect of LBH589 on NLRP3 inflammasome activation.
• To elucidate the underlying molecular mechanisms of LBH589's anti-inflammatory action in ARDS.
• To evaluate the therapeutic potential of LBH589 in a mouse model of ARDS.

Main Methods:

• Utilized LPS-primed and ATP-stimulated J774A.1 cells and bone marrow-derived macrophages (BMDMs) to assess NLRP3 inflammasome activation.
• Measured cleaved caspase-1, IL-1β, IL-18, IL-16, GSDMD cleavage, ASC speck formation, mitochondrial ROS (mtROS), and oxidized mitochondrial DNA (Ox-mtDNA).
• Administered LBH589 prophylactically and therapeutically in a lipopolysaccharide (LPS)-induced ARDS mouse model.

Main Results:

• LBH589 significantly suppressed NLRP3 inflammasome activation, evidenced by reduced cleaved caspase-1, IL-1β, IL-18, and IL-16.
• LBH589 attenuated GSDMD-mediated pyroptosis and ASC speck formation, decreasing mtROS and Ox-mtDNA.
• Both prophylactic and therapeutic LBH589 treatment inhibited pro-inflammatory cytokine secretion and ameliorated LPS-induced ARDS in mice.

Conclusions:

• LBH589 effectively inhibits NLRP3 inflammasome activation and pyroptosis by reducing key triggers like mtROS and Ox-mtDNA.
• LBH589 demonstrates significant therapeutic benefits in an ARDS mouse model, reducing inflammation and disease severity.
• LBH589 presents a promising therapeutic candidate for treating acute respiratory distress syndrome.