Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis
© 2024. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
Respiratory research - 25(2024), 1 vom: 24. Feb., Seite 100 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hu, Xingxing [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.02.2024 Date Revised 27.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s12931-024-02740-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368921298 |
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| 245 | 1 | 0 | |a Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis |
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| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acute Lung Injury (ALI) | |
| 650 | 4 | |a Basic helix-loop-helix family member e40 (Bhlhe40) | |
| 650 | 4 | |a Gasdermin D (GSDMD) | |
| 650 | 4 | |a Macrophage | |
| 650 | 4 | |a Pyroptosis | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Caspases |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 650 | 7 | |a Bhlhe40 protein, mouse |2 NLM | |
| 650 | 7 | |a Homeodomain Proteins |2 NLM | |
| 650 | 7 | |a Basic Helix-Loop-Helix Transcription Factors |2 NLM | |
| 700 | 1 | |a Zou, Menglin |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Weishuai |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Minghui |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Qinhui |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Han |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Zhenshun |e verfasserin |4 aut | |
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