Ma Wei, Ao Shengxiang, Zhou Jianping, Li Jiaxin, Liang Xin, Yang Xue, Zhang Hao, Liu Boyang, Tang Wanqi, Liu Haoru, Xiao Hongyan, Liang Huaping, Yang Xia
Department of Wound Infection and Drug, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, PR China.
College of Basic Medical Sciences, Panzihua University, Panzihua 617000, PR China.
Mol Immunol. 2022 Jun;146:69-77. doi: 10.1016/j.molimm.2022.04.001. Epub 2022 Apr 20.
Multi-drug-resistant bacterial infections, which have become a global threat, lack effective treatments. The discoveries of non-antibiotics with different modes of antibacterial action, such as methylsulfonylmethane (MSM), are a promising new treatment for multi-drug-resistant pathogens.
We constructed a mouse peritonitis infection model to evaluate the effects of MSM against methicillin-resistant Staphylococcus aureus (MRSA) infection. The time-kill kinetics of MSM against MRSA and the effect of MSM on the integrity of bacterial cell membrane were measured. Viability effects of MSM on THP1 cells were performed by CCK-8 cytotoxicity assay. Systematic inflammatory factor levels of mice were detected using ELISA. The immune response of peritoneal macrophages during MRSA-infection was evaluated using RNA sequencing. Gene Ontology function, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, and correlation analyses were applied to analysis RNA sequencing data. RT-qPCR, western blotting and flow cytometry were performed to analysis the gene and protein expression levels of macrophages.
In in vitro experiments, MSM did not show significant killing effects on the growth of MRSA directly and did not destroy bacterial membrane integrity. MSM also displayed no significant effects on the proliferative capacity of THP1 cells. However, MSM treatment protected mice against a lethal dose MRSA-infection and decreased systemic inflammation. MSM upregulated metabolic pathway in peritoneal macrophages, especial glycolysis, during MRSA infection. MSM increased the expression of M2 markers (such as Arg1), promoted phosphorylation of STAT3 (which regulates M2 polarization), and decreased the expression of M1 markers in peritoneal macrophages. Additionally, MSM treatment increased the expression of H3K18 lactylation specific target genes, including Arg1. GNE-140, the LDHA-specific inhibitor of glycolysis, blocked the MSM-induced Arg1 expression in this disease model.
MSM protects against MRSA infection through immunomodulation. MSM promotes the expression of Arg1 by lactate-H3K18la pathway to control macrophage to M2 polarization; it firstly provides therapeutic potential for drug-resistant infections and sepsis.
多重耐药细菌感染已成为全球威胁，且缺乏有效的治疗方法。发现具有不同抗菌作用模式的非抗生素，如甲基磺酰甲烷（MSM），是治疗多重耐药病原体的一种有前景的新方法。
我们构建了小鼠腹膜炎感染模型，以评估MSM对耐甲氧西林金黄色葡萄球菌（MRSA）感染的影响。测定了MSM对MRSA的时间杀菌动力学以及MSM对细菌细胞膜完整性的影响。通过CCK-8细胞毒性试验检测MSM对THP1细胞的活力影响。使用ELISA检测小鼠的系统性炎症因子水平。利用RNA测序评估MRSA感染期间腹膜巨噬细胞的免疫反应。应用基因本体功能、京都基因与基因组百科全书通路富集分析以及相关性分析来分析RNA测序数据。进行RT-qPCR、蛋白质印迹和流式细胞术以分析巨噬细胞的基因和蛋白质表达水平。
在体外实验中，MSM对MRSA的生长没有直接显著的杀伤作用，也没有破坏细菌膜的完整性。MSM对THP1细胞的增殖能力也没有显著影响。然而，MSM治疗可保护小鼠免受致死剂量的MRSA感染，并减轻全身炎症。在MRSA感染期间，MSM上调了腹膜巨噬细胞中的代谢途径，尤其是糖酵解。MSM增加了M2标志物（如Arg1）的表达，促进了STAT3（调节M2极化）的磷酸化，并降低了腹膜巨噬细胞中M1标志物的表达。此外，MSM治疗增加了H3K18乳酸化特异性靶基因的表达，包括Arg1。GNE-140，一种糖酵解的LDHA特异性抑制剂，在该疾病模型中阻断了MSM诱导的Arg1表达。
MSM通过免疫调节预防MRSA感染。MSM通过乳酸-H3K18la途径促进Arg 的表达，以控制巨噬细胞向M2极化；它首先为耐药感染和败血症提供了治疗潜力。
