Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis
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 infl...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-024-02740-2 |
| _version_ | 1797273565866754048 |
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| author | Xingxing Hu Menglin Zou Weishuai Zheng Minghui Zhu Qinhui Hou Han Gao Xin Zhang Yuan Liu Zhenshun Cheng |
| author_facet | Xingxing Hu Menglin Zou Weishuai Zheng Minghui Zhu Qinhui Hou Han Gao Xin Zhang Yuan Liu Zhenshun Cheng |
| author_sort | Xingxing Hu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:45:15Z |
| format | Article |
| id | doaj.art-f586f7bb603f446ba607e97c49c4d083 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-03-07T14:45:15Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-f586f7bb603f446ba607e97c49c4d0832024-03-05T20:02:28ZengBMCRespiratory Research1465-993X2024-02-0125111310.1186/s12931-024-02740-2Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosisXingxing Hu0Menglin Zou1Weishuai Zheng2Minghui Zhu3Qinhui Hou4Han Gao5Xin Zhang6Yuan Liu7Zhenshun Cheng8Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityFourth Ward of Medical Care Center, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical UniversityDepartment of Respiratory and Critical Care Medicine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityDepartment of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan UniversityAbstract 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.https://doi.org/10.1186/s12931-024-02740-2Acute Lung Injury (ALI)Basic helix-loop-helix family member e40 (Bhlhe40)MacrophageGasdermin D (GSDMD)Pyroptosis |
| spellingShingle | Xingxing Hu Menglin Zou Weishuai Zheng Minghui Zhu Qinhui Hou Han Gao Xin Zhang Yuan Liu Zhenshun Cheng Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis Respiratory Research Acute Lung Injury (ALI) Basic helix-loop-helix family member e40 (Bhlhe40) Macrophage Gasdermin D (GSDMD) Pyroptosis |
| title | Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis |
| title_full | Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis |
| title_fullStr | Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis |
| title_full_unstemmed | Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis |
| title_short | Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis |
| title_sort | bhlhe40 deficiency attenuates lps induced acute lung injury through preventing macrophage pyroptosis |
| topic | Acute Lung Injury (ALI) Basic helix-loop-helix family member e40 (Bhlhe40) Macrophage Gasdermin D (GSDMD) Pyroptosis |
| url | https://doi.org/10.1186/s12931-024-02740-2 |
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