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Updated: Apr 25, 2026
Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages
Published on: June 23, 2013
SIRT6-mediated immunometabolic reprogramming of macrophages drives neutrophilic asthma via LDHA-dependent glycolysis
Guomei Su1, Jiangyun Peng2, Jingyun Quan1
1Dongguan Key Laboratory of Immune Inflammation and Metabolism, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China; Department of Respiratory and Critical Care Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China.
Abstract:
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.
