SIRT6-mediated immunometabolic reprogramming of macrophages drives neutrophilic asthma via LDHA-dependent glycolysis.
Fuente:
PubMed
Gespeichert in:
| Hauptverfasser: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Artículo científico |
| Sprache: | en |
| Veröffentlicht: |
Cell reports
2026
|
| Schlagworte: | |
| Online-Zugang: | |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| _version_ | 1868266056191049730 |
|---|---|
| author | Su, Guomei Peng, Jiangyun Quan, Jingyun Feng, Zhihang Zhong, Yu Xiong, Zhilin Huang, Jiewen Zhao, Zhao Lv, Yingying Hou, Wenhong Luo, Lianxiang Li, Xiao Shao, Yiming Duan, Jielin Gao, Xiao Lai, Tianwen |
| author_facet | Su, Guomei Peng, Jiangyun Quan, Jingyun Feng, Zhihang Zhong, Yu Xiong, Zhilin Huang, Jiewen Zhao, Zhao Lv, Yingying Hou, Wenhong Luo, Lianxiang Li, Xiao Shao, Yiming Duan, Jielin Gao, Xiao Lai, Tianwen Su, Guomei Peng, Jiangyun Quan, Jingyun Feng, Zhihang Zhong, Yu Xiong, Zhilin Huang, Jiewen Zhao, Zhao Lv, Yingying Hou, Wenhong Luo, Lianxiang Li, Xiao Shao, Yiming Duan, Jielin Gao, Xiao Lai, Tianwen |
| collection | PubMed - marine biology |
| contents | SIRT6-mediated immunometabolic reprogramming of macrophages drives neutrophilic asthma via LDHA-dependent glycolysis. Su, Guomei Peng, Jiangyun Quan, Jingyun Feng, Zhihang Zhong, Yu Xiong, Zhilin Huang, Jiewen Zhao, Zhao Lv, Yingying Hou, Wenhong Luo, Lianxiang Li, Xiao Shao, Yiming Duan, Jielin Gao, Xiao Lai, Tianwen Sirtuins Animals Asthma Humans Neutrophils Macrophages Glycolysis Mice Lactate Dehydrogenase 5 Metabolic Reprogramming Mice, Inbred C57BL Neutrophil Infiltration Neutrophilic asthma is a steroid-resistant condition linked to immunometabolic dysregulation. While the NAD-dependent deacetylase Sirtuin 6 (SIRT6) regulates immune responses, its role in neutrophilic asthma remains unknown. Utilizing multiple human samples and neutrophilic asthma murine model, we identify macrophage SIRT6 as a key regulator that governs airway neutrophil infiltration in severe asthma. Myeloid-specific Sirt6 deletion attenuates allergen-induced airway neutrophil infiltration by suppressing lactate dehydrogenase A (LDHA)-mediated lactate production and neutrophil-recruiting chemokines secretion. Mechanistically, SIRT6 directly interacts with LDHA and deacetylates LDHA at lysine 261 (K261) via SIRT6-N-terminal domain. Lactate accumulation promotes histone H4 lysine 12 (H4K12) lactylation, up-regulating Cxcl1 and Cxcl2 transcription to drive airway neutrophil infiltration. Importantly, we screen flavonoid astragalin as a specific SIRT6 inhibitor that attenuates airway neutrophil infiltration in severe asthmatic mice. Collectively, our findings reveal a critical role of the SIRT6-mediated metabolic reprogramming in neutrophilic asthma and establish SIRT6 as a promising therapeutic target. |
| format | Artículo científico |
| id | pubmed_42024501 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | Cell reports |
| record_format | pubmed |
| spellingShingle | SIRT6-mediated immunometabolic reprogramming of macrophages drives neutrophilic asthma via LDHA-dependent glycolysis. Su, Guomei Peng, Jiangyun Quan, Jingyun Feng, Zhihang Zhong, Yu Xiong, Zhilin Huang, Jiewen Zhao, Zhao Lv, Yingying Hou, Wenhong Luo, Lianxiang Li, Xiao Shao, Yiming Duan, Jielin Gao, Xiao Lai, Tianwen Sirtuins Animals Asthma Humans Neutrophils Macrophages Glycolysis Mice Lactate Dehydrogenase 5 Metabolic Reprogramming Mice, Inbred C57BL Neutrophil Infiltration SIRT6-mediated immunometabolic reprogramming of macrophages drives neutrophilic asthma via LDHA-dependent glycolysis. Su, Guomei Peng, Jiangyun Quan, Jingyun Feng, Zhihang Zhong, Yu Xiong, Zhilin Huang, Jiewen Zhao, Zhao Lv, Yingying Hou, Wenhong Luo, Lianxiang Li, Xiao Shao, Yiming Duan, Jielin Gao, Xiao Lai, Tianwen Sirtuins Animals Asthma Humans Neutrophils Macrophages Glycolysis Mice Lactate Dehydrogenase 5 Metabolic Reprogramming Mice, Inbred C57BL Neutrophil Infiltration Neutrophilic asthma is a steroid-resistant condition linked to immunometabolic dysregulation. While the NAD-dependent deacetylase Sirtuin 6 (SIRT6) regulates immune responses, its role in neutrophilic asthma remains unknown. Utilizing multiple human samples and neutrophilic asthma murine model, we identify macrophage SIRT6 as a key regulator that governs airway neutrophil infiltration in severe asthma. Myeloid-specific Sirt6 deletion attenuates allergen-induced airway neutrophil infiltration by suppressing lactate dehydrogenase A (LDHA)-mediated lactate production and neutrophil-recruiting chemokines secretion. Mechanistically, SIRT6 directly interacts with LDHA and deacetylates LDHA at lysine 261 (K261) via SIRT6-N-terminal domain. Lactate accumulation promotes histone H4 lysine 12 (H4K12) lactylation, up-regulating Cxcl1 and Cxcl2 transcription to drive airway neutrophil infiltration. Importantly, we screen flavonoid astragalin as a specific SIRT6 inhibitor that attenuates airway neutrophil infiltration in severe asthmatic mice. Collectively, our findings reveal a critical role of the SIRT6-mediated metabolic reprogramming in neutrophilic asthma and establish SIRT6 as a promising therapeutic target. |
| title | SIRT6-mediated immunometabolic reprogramming of macrophages drives neutrophilic asthma via LDHA-dependent glycolysis. |
| topic | Sirtuins Animals Asthma Humans Neutrophils Macrophages Glycolysis Mice Lactate Dehydrogenase 5 Metabolic Reprogramming Mice, Inbred C57BL Neutrophil Infiltration |
| url | https://pubmed.ncbi.nlm.nih.gov/42024501/ |