S100a9 lactylation triggers neutrophil trafficking and cardiac inflammation in myocardial ischemia/reperfusion injury
Xiaoqi Wang, Xiangyu Yan, Ge Mang, Yujia Chen, Shuang Liu, Jiayu Sui, Zhonghua Tong, Penghe Wang, Jingxuan Cui, Qiannan Yang, Yafei Zhang, Dongni Wang, Ping Sun, Weijun Song, Zexi Jin, Ming Shi, Peng Zhao, Jia Yang, Mingyang Liu, Naixin Wang, Tao Chen, Yong Ji, Bo Yu, Maomao Zhang
Xiaoqi Wang, Xiangyu Yan, Ge Mang, Yujia Chen, Shuang Liu, Jiayu Sui, Zhonghua Tong, Penghe Wang, Jingxuan Cui, Qiannan Yang, Yafei Zhang, Dongni Wang, Ping Sun, Weijun Song, Zexi Jin, Ming Shi, Peng Zhao, Jia Yang, Mingyang Liu, Naixin Wang, Tao Chen, Yong Ji, Bo Yu, Maomao Zhang
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Research Article Cardiology Immunology

S100a9 lactylation triggers neutrophil trafficking and cardiac inflammation in myocardial ischemia/reperfusion injury

Abstract

Lactylation, a posttranslational modification derived from glycolysis, plays a pivotal role in ischemic heart disease. Neutrophils are predominantly glycolytic cells that trigger intensive inflammation of myocardial ischemia/reperfusion (MI/R). However, whether lactylation regulates neutrophil function during MI/R remains unknown. We applied lactyl proteomics analysis and found that S100a9 was lactylated at lysine 26 (S100a9K26la) in neutrophils, with elevated levels observed in both patients with acute myocardial infarction (AMI) and MI/R model mice. We demonstrated that S100a9K26la drove the development of MI/R using mutant knockin mice. Mechanistically, lactylated S100a9 translocated to the nucleus of neutrophils, where it bound to the promoters of migration-related genes, thereby enhancing their transcription as a coactivator and promoting neutrophil migration and cardiac recruitment. Additionally, lactylated S100a9 was released during neutrophil extracellular trap (NET) formation, leading to cardiomyocyte death by disrupting mitochondrial function. The enzyme dihydrolipoyllysine-residue acetyltransferase (DLAT) was identified as the lactyltransferase facilitating neutrophil S100a9K26la following MI/R, a process that could be restrained by α-lipoic acid. Consistently, we found that targeting the DLAT/S100a9K26la axis suppressed neutrophil burden and improved cardiac function following MI/R. In patients with AMI, elevated S100a9K26la levels in plasma were positively correlated with cardiac death. These findings highlight S100a9 lactylation as a potential therapeutic target for MI/R and as a promising biomarker for evaluating poor MI/R outcomes.

Authors

Xiaoqi Wang, Xiangyu Yan, Ge Mang, Yujia Chen, Shuang Liu, Jiayu Sui, Zhonghua Tong, Penghe Wang, Jingxuan Cui, Qiannan Yang, Yafei Zhang, Dongni Wang, Ping Sun, Weijun Song, Zexi Jin, Ming Shi, Peng Zhao, Jia Yang, Mingyang Liu, Naixin Wang, Tao Chen, Yong Ji, Bo Yu, Maomao Zhang

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Figure 2

Deletion of S100a9K26-specific lactylation improves post-MI/R cardiac function.

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Deletion of S100a9K26-specific lactylation improves post-MI/R cardiac fu...
(A) Strategy for generating S100a9K26R-mutant mice and amino acid alterations at the S100a9 mutation site. (B) Nucleotide mutation site in the S100a9K26R mice. (C) H&E staining of heart tissue 3 days after MI/R (scale bars: 1 mm; n = 6). (D and E) Fibrotic area quantification and Masson’s trichrome staining 14 days after MI/R (scale bars: 1 mm; n = 6). Data indicate the mean ± SD. **P < 0.01 and ****P < 0.0001 for the indicated comparisons in E, by 1-way ANOVA with Tukey’s multiple-comparison test (P values were adjusted for 6 comparisons). (F and G) Representative B- and M-mode echocardiograms with measurements on day 14 after MI/R (n = 8). Data indicate the mean ± SD. *P < 0.05, ***P < 0.001, and ****P < 0.0001 for the indicated comparisons in G, by 2-way ANOVA with Tukey’s multiple-comparison test (P values were adjusted for 6 comparisons). (H) Schematic representation of the BMT protocol: BM samples from WT and S100a9K26R mice were transplanted into WT recipients and allowed to reconstitute for 6 weeks, after which the mice were subjected to MI/R. Neutrophil-specific S100a9K26R and WT mice were injected with 100 μL rS100a9 (1.5 mg/kg/BW) 4 hours after MI/R, and other control mice were injected with the same volume of saline. (I–K) H&E-stained images (I), Masson’s trichrome–stained images (J), and fibrotic area quantification (K) of the heart after MI/R. Scale bars: 1 mm (I and J). n = 6 (I–K). (L and M) Representative M-mode echocardiograms (L) with measurements of EF, FS, diastolic LVID (dLVID), and systolic LVID (sLVID) (M) (n = 8). Data indicate the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 for the indicated comparisons in K and M, by 1-way ANOVA with Tukey’s multiple-comparison test (P values were adjusted for 6 comparisons).