Otálora-Alcaraz Almudena, Reilly Thomas, Oró-Nolla Martí, Sun Melody Cui, Costelloe Lisa, Kearney Hugh, Patra Pabitra H, Downer Eric J
Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Department of Neurology, Beaumont Hospital, Dublin, Ireland.
Biochem Pharmacol. 2025 Feb;232:116667. doi: 10.1016/j.bcp.2024.116667. Epub 2024 Dec 7.
Multiple sclerosis (MS) is a neurological autoimmune condition associated with many symptoms including spasticity, pain, limb numbness and weakness. It is characterised by inflammatory demyelination and axonal degeneration of the brain and spinal cord. A range of disease-modifying therapies (DMTs) are available to suppress inflammatory disease activity in MS, however, there is a pressing need for new therapeutic avenues as DMTs have a limited ability to suppress confirmed disability progression. A body of literature indicates that innate immune inflammation is linked to MS progression. The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing protein 3 (NLRP3) inflammasome has a well-established function in innate immunity which is closely associated with the pathogenesis of neuroinflammatory conditions. Evidence suggests that the inflammasome may be a therapeutic target in disorders such as MS and at present, inhibitors of the NLRP3 inflammasome are in pre-clinical development. Therefore, this review systematically highlights the pathogenic role of inflammasomes in MS, presenting an overview of research evidence linking inflammasome-related polymorphisms to MS susceptibility, and gathering evidence investigating NLRP3 biomarkers in MS. The role of the NLRP3 inflammasome in murine models of MS is furthermore discussed. Finally, a significant component of this review focuses on evidence that NLRP3 signalling components are novel drug targets in MS. Overall this review defines the role of the inflammasome in MS pathogenesis and identifies inflammasome inhibitor targets that warrant full investigation in MS and related disorders.
多发性硬化症（MS）是一种神经自身免疫性疾病，伴有多种症状，包括痉挛、疼痛、肢体麻木和无力。其特征是脑和脊髓的炎症性脱髓鞘和轴突变性。目前有一系列疾病修正疗法（DMTs）可用于抑制MS中的炎症性疾病活动，然而，由于DMTs抑制已确诊残疾进展的能力有限，迫切需要新的治疗途径。大量文献表明，先天性免疫炎症与MS进展有关。含核苷酸结合寡聚化结构域（NOD）样受体吡啉结构域蛋白3（NLRP3）炎性小体在先天性免疫中具有明确的功能，这与神经炎症性疾病的发病机制密切相关。有证据表明，炎性小体可能是MS等疾病的治疗靶点，目前，NLRP3炎性小体抑制剂正处于临床前开发阶段。因此，本综述系统地强调了炎性小体在MS中的致病作用，概述了将炎性小体相关多态性与MS易感性联系起来的研究证据，并收集了调查MS中NLRP3生物标志物的证据。此外，还讨论了NLRP3炎性小体在MS小鼠模型中的作用。最后，本综述的一个重要部分聚焦于NLRP3信号成分是MS中新的药物靶点的证据。总体而言，本综述定义了炎性小体在MS发病机制中的作用，并确定了炎性小体抑制剂靶点，这些靶点值得在MS和相关疾病中进行全面研究。
