Background Immunometabolism exerts a bimodal action at the interface of extracellular immune response and intracellular metabolism. It controls both intracellular processes and extracellular inflammatory responses by regulating both cellular energy supply & demands, factors that determine how a cell responds to the extracellular signals. Hence, immunometabolic pathways represent an attractive target as a gate of entry & checkpoint for the inflammatory cascade. Nucleotide-binding oligomerization domain, Leucine Rich repeat containing X1 (NLRX1) & PLeXin Domain-Containing protein 2 (PLXDC2) have been identified in immunometabolic pathways for multiple cell types in immune mediated inflammatory diseases (IMIDs) and inflammatory bowel diseases (IBD)2,3. The goal of this analysis was to compare these two key immunometabolic pathways. Methods For both programs, in vitro murine T cell & macrophage differentiation & in vivo mouse dextran sodium sulfate (DSS) colitis models, gene expression, metabolic profiles & cytokine expression were assessed. Results NX-13, a novel NLRX1 agonist, resulted in regulation of cellular metabolism: activation of mitochondrial genes such as mt-nd3 & odgh, and concomitant down-regulation of glucose uptake by murine T cells (Fig1A). Simultaneously, NLRX1 stabilization by NX-13 increased antioxidant enzyme expression & reduced reactive oxygen species in T cells. NX-13 specifically reduced effector T cell differentiation (Fig1B) & inflammatory cytokine expression, while Treg differentiation was increased. Ultimately, these bimodal effects converge to dampened colitis severity scores in acute DSS colitis (Fig1C). PLXDC2 activation by LABP-69 directly reduced glycolysis, reflected by decreased extracellular acidification & oxygen consumption in bone marrow-derived macrophages (BMDM) stimulated with lipopolysaccharide (LPS, Fig1D). LABP-69 also reduced superoxide levels in BMDM. Of note, PLXDC2 activation downregulated cellular expression of the inflammatory cytokines TNFα & IFNγ by T cells (Fig1E). The PLXDC2 agonist PX-04 decreased inflammation in acute DSS colitis in mice as shown by disease activity score (Fig1F). Conclusion Agents targeting immunometabolism demonstrate a novel, innovative concept with potential therapeutic applicability in IBD & other IMID. NLRX1 & PLXDC2 represent distinct pathways that modulate the intracellular metabolic state simultaneously with extracellular inflammation and hence can be targeted to break the inflammatory cascade to stop chronic inflammation. These bimodal MOAs will be studied further to understand how they may synergistically address multiple aspects of chronic immune diseases such as IBD. 1Chi Cell Mol Immunol (19) 2Leber et al. J Immunol 203(12) 3Tubau-Juni et al. J Immunol 206(Supp)

中文翻译：

---

P144 通过 NLRX1 或 PLXDC2 调节免疫代谢：治疗炎症性肠病的新型双模式机制

背景免疫代谢在细胞外免疫反应和细胞内代谢的界面上发挥双峰作用。它通过调节细胞能量供应和需求（决定细胞如何响应细胞外信号的因素）来控制细胞内过程和细胞外炎症反应。因此，免疫代谢途径代表了一个有吸引力的目标，作为炎症级联的入口和检查点。核苷酸结合寡聚化结构域、含有 X1 的富含亮氨酸重复序列 (NLRX1) 和含有 PLeXin 结构域的蛋白 2 (PLXDC2) 已在免疫介导的炎症性疾病 (IMID) 和炎症性肠病 (IBD) 的多种细胞类型的免疫代谢途径中得到鉴定2 ,3. 该分析的目的是比较这两个关键的免疫代谢途径。方法对于这两个项目，均评估了体外小鼠 T 细胞和巨噬细胞分化以及体内小鼠右旋糖酐硫酸钠 (DSS) 结肠炎模型、基因表达、代谢谱和细胞因子表达。结果 NX-13 是一种新型 NLRX1 激动剂，可调节细胞代谢：激活线粒体基因（如 mt-nd3 和 odgh），并同时下调小鼠 T 细胞的葡萄糖摄取（图 1A）。同时，NX-13 对 NLRX1 的稳定作用增加了 T 细胞中抗氧化酶的表达并减少了活性氧。NX-13 特异性降低效应 T 细胞分化（图 1B）和炎症细胞因子表达，同时 Treg 分化增加。最终，这些双峰效应会导致急性 DSS 结肠炎的结肠炎严重程度评分下降（图 1C）。LABP-69 激活 PLXDC2 直接减少糖酵解，这反映在用脂多糖（LPS，图 1D）刺激的骨髓源性巨噬细胞（BMDM）中细胞外酸化和耗氧量减少。LABP-69 还降低了 BMDM 中的超氧化物水平。值得注意的是，PLXDC2 激活下调了 T 细胞炎症细胞因子 TNFα 和 IFNγ 的细胞表达（图 1E）。PLXDC2 激动剂 PX-04 减少了小鼠急性 DSS 结肠炎的炎症，如疾病活动评分所示（图 1F）。结论 靶向免疫代谢的药物展示了一种新颖、创新的概念，在 IBD 和其他 IMID 中具有潜在的治疗适用性。NLRX1 和 PLXDC2 代表了与细胞外炎症同时调节细胞内代谢状态的不同途径，因此可以有针对性地打破炎症级联反应以阻止慢性炎症。这些双峰 MOA 将得到进一步研究，以了解它们如何协同解决 IBD 等慢性免疫疾病的多个方面。1Chi 细胞分子免疫学 (19) 2Leber 等人。J 免疫学杂志 203(12) 3Tubau-Juni 等人。J 免疫学杂志 206（增刊）