The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK.
J Neurochem. 2024 Sep;168(9):3333-3357. doi: 10.1111/jnc.16015. Epub 2023 Dec 16.
Although the central nervous system (CNS) and immune system were regarded as independent entities, it is now clear that immune system cells can influence the CNS, and neuroglial activity influences the immune system. Despite the many clinical implications for this 'neuroimmune interface', its detailed operation at the molecular level remains unclear. This narrative review focuses on the metabolism of tryptophan along the kynurenine pathway, since its products have critical actions in both the nervous and immune systems, placing it in a unique position to influence neuroimmune communication. In particular, since the kynurenine pathway is activated by pro-inflammatory mediators, it is proposed that physical and psychological stressors are the stimuli of an organismal protective reflex, with kynurenine metabolites as the effector arm co-ordinating protective neural and immune system responses. After a brief review of the neuroimmune interface, the general perception of tryptophan metabolism along the kynurenine pathway is expanded to emphasize this environmentally driven perspective. The initial enzymes in the kynurenine pathway include indoleamine-2,3-dioxygenase (IDO1), which is induced by tissue damage, inflammatory mediators or microbial products, and tryptophan-2,3-dioxygenase (TDO), which is induced by stress-induced glucocorticoids. In the immune system, kynurenic acid modulates leucocyte differentiation, inflammatory balance and immune tolerance by activating aryl hydrocarbon receptors and modulates pain via the GPR35 protein. In the CNS, quinolinic acid activates N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors, whereas kynurenic acid is an antagonist: the balance between glutamate, quinolinic acid and kynurenic acid is a significant regulator of CNS function and plasticity. The concept of kynurenine and its metabolites as mediators of a reflex coordinated protection against stress helps to understand the variety and breadth of their activity. It should also help to understand the pathological origin of some psychiatric and neurodegenerative diseases involving the immune system and CNS, facilitating the development of new pharmacological strategies for treatment.
尽管中枢神经系统 (CNS) 和免疫系统被认为是独立的实体，但现在很清楚，免疫系统细胞可以影响中枢神经系统，而神经胶质活动会影响免疫系统。尽管这种“神经免疫界面”具有许多临床意义，但它在分子水平上的详细运作仍不清楚。本综述重点介绍色氨酸沿犬尿酸途径的代谢，因为其产物在神经系统和免疫系统中都具有关键作用，使其处于影响神经免疫通讯的独特位置。特别是，由于犬尿酸途径被促炎介质激活，因此可以假设身体和心理应激源是生物体保护性反射的刺激物，犬尿酸代谢物作为协调保护性神经和免疫系统反应的效应臂。在简要回顾神经免疫界面之后，扩展了对犬尿酸途径中色氨酸代谢的一般认识，以强调这种由环境驱动的观点。犬尿酸途径的初始酶包括吲哚胺 2,3-双加氧酶 (IDO1)，它被组织损伤、炎症介质或微生物产物诱导，而色氨酸 2,3-双加氧酶 (TDO) 则被应激诱导的糖皮质激素诱导。在免疫系统中，犬尿酸通过激活芳烃受体来调节白细胞分化、炎症平衡和免疫耐受，并通过 GPR35 蛋白来调节疼痛。在中枢神经系统中，喹啉酸激活 N-甲基-D-天冬氨酸 (NMDA) 敏感型谷氨酸受体，而犬尿酸是其拮抗剂：谷氨酸、喹啉酸和犬尿酸之间的平衡是中枢神经系统功能和可塑性的重要调节剂。将犬尿酸及其代谢物作为应激协调保护反射的介质的概念有助于理解其多样性和广泛的活性。它还有助于理解涉及免疫系统和中枢神经系统的一些精神和神经退行性疾病的病理起源，为治疗开发新的药理学策略。
