State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Pharmacol Ther. 2021 Nov;227:107880. doi: 10.1016/j.pharmthera.2021.107880. Epub 2021 Apr 24.
Inflammasomes are multi-protein macromolecular complexes that typically comprise of three units, a sensor, an adaptor and procaspase-1. The assembly of each inflammasome is dictated by a unique pattern recognition receptors (PRRs) in response to pathogen-associated molecular patterns (PAMPs) or other endogenous danger-associated molecular patterns (DAMPs) in the cytosol of the host cells, and promote the maturation and secretion of IL-1β and IL-18 during the inflammatory process. Specific inflammasomes are involved in the host defense response against different pathogens, and the latter have evolved multiple corresponding mechanisms to inhibit inflammasome activation. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome is the best understood in terms of molecular mechanisms, and is a promising therapeutic target in immune-related disorders. Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination of white matter in the central nervous system, increased levels of IL-1β in the cerebrospinal fluid (CSF) of relapsed patients, and deposition of caspase-1 in the spinal cord. The direct involvement of the NLRP3 inflammasome in the occurrence and development of MS was ascertained in the experimental autoimmune encephalomyelitis (EAE) animal model. In this review, we have focused on the mechanisms underlying activation of the NLRP3 inflammasome in MS or EAE, as well as inhibitors that specifically target the complex and alleviate disease progression, in order to unearth new therapeutic strategies against MS.
炎症小体是一种多蛋白大分子复合物，通常由三个单元组成，分别是传感器、衔接蛋白和前胱天蛋白酶-1。每个炎症小体的组装是由宿主细胞胞质中的独特模式识别受体（PRRs）对病原体相关分子模式（PAMPs）或其他内源性危险相关分子模式（DAMPs）的反应所决定的，并在炎症过程中促进白细胞介素-1β和白细胞介素-18 的成熟和分泌。特定的炎症小体参与宿主对不同病原体的防御反应，而后者已经进化出多种相应的机制来抑制炎症小体的激活。核苷酸结合寡聚化结构域富含亮氨酸重复序列和吡喃结构域蛋白 3（NLRP3）炎症小体在分子机制方面的研究最为深入，是免疫相关疾病有前途的治疗靶点。多发性硬化症（MS）是一种自身免疫性疾病，其特征是中枢神经系统白质的炎症性脱髓鞘，复发患者脑脊液（CSF）中白细胞介素-1β水平升高，以及脊髓中 caspase-1 的沉积。在实验性自身免疫性脑脊髓炎（EAE）动物模型中，确定了 NLRP3 炎症小体在 MS 发生和发展中的直接参与。在这篇综述中，我们重点关注了 MS 或 EAE 中 NLRP3 炎症小体激活的机制，以及专门针对该复合物的抑制剂，以减轻疾病进展，从而为 MS 寻找新的治疗策略。
