{"title":"类风湿性关节炎的代谢检查点。","authors":"Cornelia M Weyand, Jörg J Goronzy","doi":"10.1016/j.semarthrit.2024.152586","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Rheumatoid Arthritis is a systemic autoimmune disease affecting 0.5-1 % of the population. Despite a growing therapeutic armamentarium, RA remains incurable, and many patients suffer significant morbidity over time. The strongest genetic risk derives from HLA class II polymorphisms, implicating T cells as pathogenic drivers. Innate immune cells, e.g. monocytes and macrophages (Mⱷ) contribute to chronic tissue inflammation through an array of pro-inflammatory functions but also present antigen to autoreactive T cells. Differentiation, survival, and effector functions of both T cells and Mⱷ are ultimately controlled by their bioenergetic and biosynthetic programs, identifying cellular metabolism as a critical disease mechanism in RA.</p><p><strong>Objectives: </strong>Summarize current knowledge about metabolic conditions in the RA joint and disease-relevant metabolic circuits shaping the effector repertoire of RA T cells and Mⱷ.</p><p><strong>Results: </strong>The rheumatoid joint is a glucose deplete tissue environment, selecting for invading immune cells that can survive on non-glucose fuel sources. Inflamed synovium instead offers the amino acid glutamine and RA CD4<sup>+</sup>T cells and RA Mⱷ rely on glutamine and glutamate to support their pathogenic functions. The metabolic hallmark of RA T cells is their low mitochondrial performance, resulting in low ATP production, low generation of reactive oxygen species (ROS) and low availability of tricarboxylic acid (TCA) cycle intermediates, all shifting RA T cells towards autoreactivity. The underlying defect stems from insufficient repair of mitochondrial DNA (mtDNA). Functional consequences include reversal of the TCA cycle, accumulation of citrate and lack of malate production. Excessive citrate promotes cytoskeletal hyperacetylation, creating hypermigratory and tissue-invasive T cells. Surplus acetyl-CoA supports lipid droplet formation and lipotoxicity. Lack of malate production disrupts the malate-aspartate shuttle, restricts recovery of cytosolic NAD and drives the endoplasmic reticulum (ER) into expansion. The bioenergetically stressed ER accumulates TNF mRNA and turns RA T cells into TNF superproducers. ATP low production renders RA T cells susceptible to cell death, depositing highly inflammatory mtDNA in the tissue. Mitochondrial deficiency leads to a slowdown in glycolysis and pyruvate processing, such that RA CD4<sup>+</sup>T cells shunt glucose towards the pentose phosphate pathway to support nucleotide synthesis and clonal proliferation. Metabolically deprived CD4<sup>+</sup>T cells partner with Mⱷ that have highly functional mitochondria. A hallmark of RA Mⱷ is the high expression of the DNA binding protein RFX5, which co-ordinates adaptations to metabolic needs with function. RFX5 upregulates HLA-DR expression and induces the glutaminolytic enzyme glutamate dehydrogenase 1 (GLUD1), providing bioenergetic resources for antigen presentation and survival in the tissue. In essence, RA CD4<sup>+</sup>T cells and Mⱷ function in a metabolically challenging environment and rewire their cellular metabolism to survive. Metabolic adaptations promote immunostimulation and tissue inflammation, triggering and sustaining rheumatoid synovitis.</p>","PeriodicalId":21715,"journal":{"name":"Seminars in arthritis and rheumatism","volume":" ","pages":"152586"},"PeriodicalIF":4.6000,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Metabolic checkpoints in rheumatoid arthritis.\",\"authors\":\"Cornelia M Weyand, Jörg J Goronzy\",\"doi\":\"10.1016/j.semarthrit.2024.152586\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Rheumatoid Arthritis is a systemic autoimmune disease affecting 0.5-1 % of the population. Despite a growing therapeutic armamentarium, RA remains incurable, and many patients suffer significant morbidity over time. The strongest genetic risk derives from HLA class II polymorphisms, implicating T cells as pathogenic drivers. Innate immune cells, e.g. monocytes and macrophages (Mⱷ) contribute to chronic tissue inflammation through an array of pro-inflammatory functions but also present antigen to autoreactive T cells. Differentiation, survival, and effector functions of both T cells and Mⱷ are ultimately controlled by their bioenergetic and biosynthetic programs, identifying cellular metabolism as a critical disease mechanism in RA.</p><p><strong>Objectives: </strong>Summarize current knowledge about metabolic conditions in the RA joint and disease-relevant metabolic circuits shaping the effector repertoire of RA T cells and Mⱷ.</p><p><strong>Results: </strong>The rheumatoid joint is a glucose deplete tissue environment, selecting for invading immune cells that can survive on non-glucose fuel sources. Inflamed synovium instead offers the amino acid glutamine and RA CD4<sup>+</sup>T cells and RA Mⱷ rely on glutamine and glutamate to support their pathogenic functions. The metabolic hallmark of RA T cells is their low mitochondrial performance, resulting in low ATP production, low generation of reactive oxygen species (ROS) and low availability of tricarboxylic acid (TCA) cycle intermediates, all shifting RA T cells towards autoreactivity. The underlying defect stems from insufficient repair of mitochondrial DNA (mtDNA). Functional consequences include reversal of the TCA cycle, accumulation of citrate and lack of malate production. Excessive citrate promotes cytoskeletal hyperacetylation, creating hypermigratory and tissue-invasive T cells. Surplus acetyl-CoA supports lipid droplet formation and lipotoxicity. Lack of malate production disrupts the malate-aspartate shuttle, restricts recovery of cytosolic NAD and drives the endoplasmic reticulum (ER) into expansion. The bioenergetically stressed ER accumulates TNF mRNA and turns RA T cells into TNF superproducers. ATP low production renders RA T cells susceptible to cell death, depositing highly inflammatory mtDNA in the tissue. Mitochondrial deficiency leads to a slowdown in glycolysis and pyruvate processing, such that RA CD4<sup>+</sup>T cells shunt glucose towards the pentose phosphate pathway to support nucleotide synthesis and clonal proliferation. Metabolically deprived CD4<sup>+</sup>T cells partner with Mⱷ that have highly functional mitochondria. A hallmark of RA Mⱷ is the high expression of the DNA binding protein RFX5, which co-ordinates adaptations to metabolic needs with function. RFX5 upregulates HLA-DR expression and induces the glutaminolytic enzyme glutamate dehydrogenase 1 (GLUD1), providing bioenergetic resources for antigen presentation and survival in the tissue. In essence, RA CD4<sup>+</sup>T cells and Mⱷ function in a metabolically challenging environment and rewire their cellular metabolism to survive. Metabolic adaptations promote immunostimulation and tissue inflammation, triggering and sustaining rheumatoid synovitis.</p>\",\"PeriodicalId\":21715,\"journal\":{\"name\":\"Seminars in arthritis and rheumatism\",\"volume\":\" \",\"pages\":\"152586\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-11-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Seminars in arthritis and rheumatism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.semarthrit.2024.152586\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Seminars in arthritis and rheumatism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.semarthrit.2024.152586","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景:类风湿关节炎是一种全身性自身免疫疾病,发病率占总人口的 0.5-1%。尽管治疗手段越来越多,但 RA 仍无法治愈,许多患者长期以来发病率很高。最大的遗传风险来自于 HLA II 类多态性,这意味着 T 细胞是致病的驱动因素。先天性免疫细胞,如单核细胞和巨噬细胞(Mⱷ),通过一系列促炎功能对慢性组织炎症做出贡献,但也会向自反应性 T 细胞提供抗原。T细胞和Mⱷ的分化、存活和效应功能最终受其生物能和生物合成程序的控制,这表明细胞代谢是RA的一个关键疾病机制:总结目前有关RA关节中代谢状况的知识,以及影响RA T细胞和Mⱷ效应细胞群的疾病相关代谢回路:结果:类风湿关节是一个葡萄糖耗竭的组织环境,它选择了能在非葡萄糖燃料来源下生存的入侵免疫细胞。发炎的滑膜可提供氨基酸谷氨酰胺,类风湿 CD4+T 细胞和类风湿 Mⱷ 依赖谷氨酰胺和谷氨酸支持其致病功能。RA T 细胞的代谢特征是线粒体性能低下,导致 ATP 生成量低、活性氧(ROS)生成量低和三羧酸(TCA)循环中间产物供应量低,所有这些都使 RA T 细胞走向自反应。根本缺陷源于线粒体 DNA(mtDNA)修复不足。功能性后果包括 TCA 循环逆转、柠檬酸盐积累和苹果酸盐生成不足。过多的柠檬酸盐会促进细胞骨架的高乙酰化,从而产生高移行性和组织侵袭性 T 细胞。过剩的乙酰-CoA 支持脂滴的形成和脂毒性。缺乏苹果酸会破坏苹果酸-天门冬氨酸穿梭,限制细胞膜 NAD 的恢复,并促使内质网(ER)膨胀。生物能受压的内质网积累 TNF mRNA,使 RA T 细胞成为 TNF 的超级生产者。ATP 的低产使 RA T 细胞容易发生细胞死亡,并在组织中沉积高度炎性的 mtDNA。线粒体缺乏会导致糖酵解和丙酮酸处理过程减慢,从而使 RA CD4+T 细胞将葡萄糖分流到磷酸戊糖途径,以支持核苷酸合成和克隆增殖。代谢匮乏的 CD4+T 细胞与线粒体功能强大的 Mⱷ 细胞合作。RA Mⱷ的一个特征是DNA结合蛋白RFX5的高表达,RFX5能协调适应代谢需求和功能。RFX5 上调 HLA-DR 的表达,并诱导谷氨酸脱氢酶 1 (GLUD1),为抗原呈递和在组织中存活提供生物能资源。从本质上讲,RA CD4+T 细胞和 Mⱷ 在具有代谢挑战性的环境中发挥作用,并重新连接其细胞代谢以求生存。代谢适应促进免疫刺激和组织炎症,引发并维持类风湿滑膜炎。
Background: Rheumatoid Arthritis is a systemic autoimmune disease affecting 0.5-1 % of the population. Despite a growing therapeutic armamentarium, RA remains incurable, and many patients suffer significant morbidity over time. The strongest genetic risk derives from HLA class II polymorphisms, implicating T cells as pathogenic drivers. Innate immune cells, e.g. monocytes and macrophages (Mⱷ) contribute to chronic tissue inflammation through an array of pro-inflammatory functions but also present antigen to autoreactive T cells. Differentiation, survival, and effector functions of both T cells and Mⱷ are ultimately controlled by their bioenergetic and biosynthetic programs, identifying cellular metabolism as a critical disease mechanism in RA.
Objectives: Summarize current knowledge about metabolic conditions in the RA joint and disease-relevant metabolic circuits shaping the effector repertoire of RA T cells and Mⱷ.
Results: The rheumatoid joint is a glucose deplete tissue environment, selecting for invading immune cells that can survive on non-glucose fuel sources. Inflamed synovium instead offers the amino acid glutamine and RA CD4+T cells and RA Mⱷ rely on glutamine and glutamate to support their pathogenic functions. The metabolic hallmark of RA T cells is their low mitochondrial performance, resulting in low ATP production, low generation of reactive oxygen species (ROS) and low availability of tricarboxylic acid (TCA) cycle intermediates, all shifting RA T cells towards autoreactivity. The underlying defect stems from insufficient repair of mitochondrial DNA (mtDNA). Functional consequences include reversal of the TCA cycle, accumulation of citrate and lack of malate production. Excessive citrate promotes cytoskeletal hyperacetylation, creating hypermigratory and tissue-invasive T cells. Surplus acetyl-CoA supports lipid droplet formation and lipotoxicity. Lack of malate production disrupts the malate-aspartate shuttle, restricts recovery of cytosolic NAD and drives the endoplasmic reticulum (ER) into expansion. The bioenergetically stressed ER accumulates TNF mRNA and turns RA T cells into TNF superproducers. ATP low production renders RA T cells susceptible to cell death, depositing highly inflammatory mtDNA in the tissue. Mitochondrial deficiency leads to a slowdown in glycolysis and pyruvate processing, such that RA CD4+T cells shunt glucose towards the pentose phosphate pathway to support nucleotide synthesis and clonal proliferation. Metabolically deprived CD4+T cells partner with Mⱷ that have highly functional mitochondria. A hallmark of RA Mⱷ is the high expression of the DNA binding protein RFX5, which co-ordinates adaptations to metabolic needs with function. RFX5 upregulates HLA-DR expression and induces the glutaminolytic enzyme glutamate dehydrogenase 1 (GLUD1), providing bioenergetic resources for antigen presentation and survival in the tissue. In essence, RA CD4+T cells and Mⱷ function in a metabolically challenging environment and rewire their cellular metabolism to survive. Metabolic adaptations promote immunostimulation and tissue inflammation, triggering and sustaining rheumatoid synovitis.
期刊介绍:
Seminars in Arthritis and Rheumatism provides access to the highest-quality clinical, therapeutic and translational research about arthritis, rheumatology and musculoskeletal disorders that affect the joints and connective tissue. Each bimonthly issue includes articles giving you the latest diagnostic criteria, consensus statements, systematic reviews and meta-analyses as well as clinical and translational research studies. Read this journal for the latest groundbreaking research and to gain insights from scientists and clinicians on the management and treatment of musculoskeletal and autoimmune rheumatologic diseases. The journal is of interest to rheumatologists, orthopedic surgeons, internal medicine physicians, immunologists and specialists in bone and mineral metabolism.