RRC ID 78292
Author Hu X, Zou M, Zheng W, Zhu M, Hou Q, Gao H, Zhang X, Liu Y, Cheng Z.
Title Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis.
Journal Respir Res
Abstract BACKGROUND:Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) as common life-threatening lung diseases with high mortality rates are mostly associated with acute and severe inflammation in lungs. Recently, increasing evidence supports activated inflammation and gasdermin D (GSDMD)-mediated pyroptosis in macrophage are closely associated with ALI. Basic helix-loop-helix family member e40 (Bhlhe40) is a transcription factor that is comprehensively involved in inflammation. However, there is little experimental evidence connecting Bhlhe40 and GSDMD-driven pyroptosis. The study sought to verify the hypothesis that Bhlhe40 is required for GSDMD-mediated pyroptosis in lipopolysaccharide (LPS)-induced inflammatory injury.
METHOD:We performed studies using Bhlhe40-knockout (Bhlhe40 -/-) mice, small interfering RNA (siRNA) targeting Bhlhe40 and pyroptosis inhibitor disulfiram to investigate the potential roles of Bhlhe40 on LPS-induced ALI and the underlying mechanisms.
RESULTS:Bhlhe40 was highly expressed in total lung tissues and macrophages of LPS-induced mice. Bhlhe40-/- mice showed alleviative lung pathological injury and inflammatory response upon LPS stimulation. Meanwhile, we found that Bhlhe40 deficiency significantly suppressed GSDMD-mediated pyroptosis in macrophage in vivo and in vitro. By further mechanistic analysis, we demonstrated that Bhlhe40 deficiency inhibited GSDMD-mediated pyroptosis and subsequent ALI by repressing canonical (caspase-1-mediated) and non-canonical (caspase-11-mediated) signaling pathways in vivo and in vitro.
CONCLUSION:These results indicate Bhlhe40 is required for LPS-induced ALI. Bhlhe40 deficiency can inhibit GSDMD-mediated pyroptosis and therefore alleviate ALI. Targeting Bhlhe40 may be a potential therapeutic strategy for LPS-induced ALI.
Volume 25(1)
Pages 100
Published 2024-2-24
DOI 10.1186/s12931-024-02740-2
PII 10.1186/s12931-024-02740-2
PMID 38402153
PMC PMC10894472
MeSH Acute Lung Injury* / chemically induced Acute Lung Injury* / metabolism Acute Lung Injury* / prevention & control Animals Basic Helix-Loop-Helix Transcription Factors Caspases / adverse effects Homeodomain Proteins / adverse effects Inflammation Lipopolysaccharides* / toxicity Macrophages / metabolism Mice Pyroptosis RNA, Small Interfering
Mice RBRC04841