Sarkar Sujan Kumar, Gubert Carolina, Hannan Anthony J
Florey Institute of Neuroscience and Mental Health, Parkville, Australia; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia; Department of Anatomy, Histology and Physiology, Faculty of Animal Science and Veterinary Medicine, Sher-e-Bangla Agricultural University, Dhaka, Bangladesh.
Florey Institute of Neuroscience and Mental Health, Parkville, Australia; Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia.
Neurosci Biobehav Rev. 2025 Jul 3;176:106276. doi: 10.1016/j.neubiorev.2025.106276.
In various neurodegenerative disorders, inflammation and associated inflammasome activation play an important role. The most prevalent and extensively researched inflammasomes are NLRP3 inflammasomes, which are triggered by pathogens or danger signals mediating inflammatory reaction. Extracellular ATP also activates NLRP3 by stimulating the purinergic receptor P2X7 (P2X7R). Central and peripheral cells, including those in the gut, have been shown to have activated inflammasomes during pathological changes co-occurring with inflammation in various neurodegenerative disorders. Gut injury or dysfunction is increasingly recognised as one of the peripheral pathogenic characteristics of many neurodegenerative disorders, and has been found to associate with changes in gut microbes. In this article, we review data from preclinical and clinical studies regarding the involvement of the NLRP3 inflammasome and the purinergic receptor P2X7R in the pathophysiology of major CNS disorders involving neurodegeneration, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), and the most common form of motor neuron disease, amyotrophic lateral sclerosis (ALS). We also scrutinise the relationship of the NLRP3 inflammasome to intestinal microbiota alterations in these diseases. Both the NLRP3 inflammasome and P2X7R have been shown to play important roles in the pathogenesis and progression of these neurodegenerative diseases. However, most studies have focused on central nervous system (CNS) pathology, particularly within the brain, with comparatively less attention given to their contribution to gut pathology. Additionally, changes in the microbial ecosystems of the intestine have also been implicated in these disorders. However, the association between gut microbiota alterations and inflammasome activity in the pathology of these neurodegenerative disorders remains poorly understood. Therefore, further investigation is urgently needed to explore the microbiota-inflammasome-brain axis in these neurodegenerative conditions, in order to better understand their contribution to disease pathogenesis and progression, and identify novel therapeutic targets and new approaches to prevention and treatment.
在各种神经退行性疾病中，炎症及相关的炎性小体激活起着重要作用。最常见且研究最广泛的炎性小体是NLRP3炎性小体，它由介导炎症反应的病原体或危险信号触发。细胞外ATP也通过刺激嘌呤能受体P2X7（P2X7R）激活NLRP3。包括肠道细胞在内的中枢和外周细胞，在各种神经退行性疾病中与炎症同时发生的病理变化过程中，已被证明存在激活的炎性小体。肠道损伤或功能障碍越来越被认为是许多神经退行性疾病的外周致病特征之一，并且已发现其与肠道微生物的变化有关。在本文中，我们回顾了临床前和临床研究的数据，这些数据涉及NLRP3炎性小体和嘌呤能受体P2X7R在涉及神经退行性变的主要中枢神经系统疾病的病理生理学中的作用，包括阿尔茨海默病（AD）、帕金森病（PD）、多发性硬化症（MS）、亨廷顿病（HD）以及运动神经元疾病最常见的形式——肌萎缩侧索硬化症（ALS）。我们还仔细研究了这些疾病中NLRP3炎性小体与肠道微生物群改变之间的关系。NLRP3炎性小体和P2X7R在这些神经退行性疾病的发病机制和进展中均发挥重要作用。然而，大多数研究集中在中枢神经系统（CNS）病理学上，特别是在大脑内部，相对较少关注它们对肠道病理学的影响。此外，肠道微生物生态系统的变化也与这些疾病有关。然而，在这些神经退行性疾病的病理学中，肠道微生物群改变与炎性小体活性之间的关联仍知之甚少。因此，迫切需要进一步研究这些神经退行性疾病中的微生物群-炎性小体-脑轴，以便更好地了解它们对疾病发病机制和进展的作用，并确定新的治疗靶点以及预防和治疗的新方法。
