College of Veterinary Medicine, Southwest University, Chongqing, China.
College of Animal Science, South China Agricultural University, Guangzhou, China.
J Innate Immun. 2023;15(1):107-121. doi: 10.1159/000525089. Epub 2022 Jul 7.
We have previously demonstrated that Slc6a13-deficient (Slc6a13-/-; KO) mice are resistant to P. multocida infection, which might be in connection with macrophage-mediated inflammation; however, the specific metabolic mechanism is still enigmatic. Here we reproduce the less sensitive to P. multocida infection in overall survival assays as well as reduced bacterial loads, tissue lesions, and inflammation of lungs in KO mice. The transcriptome sequencing analysis of wild-type (WT) and KO mice shows a large number of differentially expressed genes that are enriched in amino acid metabolism by functional analysis. Of note, glycine levels are substantially increased in the lungs of KO mice with or without P. multocida infection in comparison to the WT controls. Interestingly, exogenous glycine supplementation alleviates P. multocida infection-induced inflammation. Mechanistically, glycine reduces the production of inflammatory cytokines in macrophages by blocking the activation of inflammasome (NALP1, NLRP3, NLRC4, AIM2, and Caspase-1). Together, Slc6a13 deficiency attenuates P. multocida infection through lessening the excessive inflammatory responses of macrophages involving glycine-inflammasome signaling.
我们之前已经证明，Slc6a13 缺陷型（Slc6a13-/-；KO）小鼠对多杀性巴氏杆菌感染具有抗性，这可能与巨噬细胞介导的炎症有关；然而，具体的代谢机制仍然难以捉摸。在这里，我们在整体存活实验中重现了 KO 小鼠对多杀性巴氏杆菌感染的敏感性降低，以及细菌负荷、组织损伤和肺部炎症减少的现象。野生型（WT）和 KO 小鼠的转录组测序分析表明，大量差异表达的基因通过功能分析富集在氨基酸代谢中。值得注意的是，与 WT 对照组相比，KO 小鼠的肺部甘氨酸水平在有无多杀性巴氏杆菌感染的情况下均显著升高。有趣的是，外源性甘氨酸补充缓解了多杀性巴氏杆菌感染引起的炎症。从机制上讲，甘氨酸通过阻断炎性小体（NALP1、NLRP3、NLRC4、AIM2 和 Caspase-1）的激活，减少了巨噬细胞中炎性细胞因子的产生。总之，Slc6a13 缺失通过减轻涉及甘氨酸-炎性小体信号的巨噬细胞过度炎症反应来减轻多杀性巴氏杆菌感染。
