Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China.
Front Immunol. 2022 Jul 1;13:920029. doi: 10.3389/fimmu.2022.920029. eCollection 2022.
Autoimmune diseases (AIDs) refer to connective tissue inflammation caused by aberrant autoantibodies resulting from dysfunctional immune surveillance. Most of the current treatments for AIDs use non-selective immunosuppressive agents. Although these therapies successfully control the disease process, patients experience significant side effects, particularly an increased risk of infection. There is a great need to study the pathogenesis of AIDs to facilitate the development of selective inhibitors for inflammatory signaling to overcome the limitations of traditional therapies. Immune cells alter their predominant metabolic profile from mitochondrial respiration to glycolysis in AIDs. This metabolic reprogramming, known to occur in adaptive immune cells, i.e., B and T lymphocytes, is critical to the pathogenesis of connective tissue inflammation. At the cellular level, this metabolic switch involves multiple signaling molecules, including serine-threonine protein kinase, mammalian target of rapamycin, and phosphoinositide 3-kinase. Although glycolysis is less efficient than mitochondrial respiration in terms of ATP production, immune cells can promote disease progression by enhancing glycolysis to satisfy cellular functions. Recent studies have shown that active glycolytic metabolism may also account for the cellular physiology of innate immune cells in AIDs. However, the mechanism by which glycolysis affects innate immunity and participates in the pathogenesis of AIDs remains to be elucidated. Therefore, we reviewed the molecular mechanisms, including key enzymes, signaling pathways, and inflammatory factors, that could explain the relationship between glycolysis and the pro-inflammatory phenotype of innate immune cells such as neutrophils, macrophages, and dendritic cells. Additionally, we summarize the impact of glycolysis on the pathophysiological processes of AIDs, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and ankylosing spondylitis, and discuss potential therapeutic targets. The discovery that immune cell metabolism characterized by glycolysis may regulate inflammation broadens the avenues for treating AIDs by modulating immune cell metabolism.
自身免疫性疾病（AIDs）是指由于免疫监视功能障碍导致异常自身抗体引起的结缔组织炎症。目前大多数 AIDs 的治疗方法都使用非选择性免疫抑制剂。虽然这些疗法成功地控制了疾病进程，但患者会出现明显的副作用，特别是感染风险增加。因此，非常有必要研究 AIDs 的发病机制，以促进开发针对炎症信号的选择性抑制剂，克服传统疗法的局限性。在 AIDs 中，免疫细胞会将其主要代谢特征从线粒体呼吸转变为糖酵解。这种代谢重编程发生在适应性免疫细胞（即 B 和 T 淋巴细胞）中，对结缔组织炎症的发病机制至关重要。在细胞水平上，这种代谢转换涉及多个信号分子，包括丝氨酸-苏氨酸蛋白激酶、哺乳动物雷帕霉素靶蛋白和磷脂酰肌醇 3-激酶。虽然糖酵解在产生 ATP 方面的效率低于线粒体呼吸，但免疫细胞可以通过增强糖酵解来满足细胞功能，从而促进疾病的进展。最近的研究表明，活性糖酵解代谢可能也是 AIDs 中固有免疫细胞的细胞生理学的原因。然而，糖酵解如何影响固有免疫以及参与 AIDs 的发病机制仍有待阐明。因此，我们综述了分子机制，包括关键酶、信号通路和炎症因子，这些机制可以解释糖酵解与固有免疫细胞（如中性粒细胞、巨噬细胞和树突状细胞）的促炎表型之间的关系。此外，我们总结了糖酵解对 AIDs 病理生理过程的影响，包括系统性红斑狼疮、类风湿关节炎、血管炎和强直性脊柱炎，并讨论了潜在的治疗靶点。发现以糖酵解为特征的免疫细胞代谢可能通过调节免疫细胞代谢来调节炎症，这为治疗 AIDs 提供了新的途径。
