Ghaffaripour Jahromi Ghazaleh, Razi Sepideh, Rezaei Nima
Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran; Universal Scientific Education and Research Network (USERN), Tehran, Iran.
Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
Brain Res. 2024 Jan 1;1822:148644. doi: 10.1016/j.brainres.2023.148644. Epub 2023 Oct 21.
Depression holds the title of the largest contributor to worldwide disability, with the numbers expected to continue growing. Currently, there are neither reliable biomarkers for the diagnosis of the disease nor are the current medications sufficient for a lasting response in nearly half of patients. In this comprehensive review, we analyze the previously established pathophysiological models of the disease and how the interplay between NLRP3 inflammasome activation and depression might offer a unifying perspective. Adopting this inflammatory theory, we explain how NLRP3 inflammasome activation emerges as a pivotal contributor to depressive inflammation, substantiated by compelling evidence from both human studies and animal models. This inflammation is found in the central nervous system (CNS) neurons, astrocytes, and microglial cells. Remarkably, dysregulation of the NLRP3 inflammasome extends beyond the CNS boundaries and permeates into the enteric and peripheral immune systems, thereby altering the microbiota-gut-brain axis. The integrity of the brain blood barrier (BBB) and intestinal epithelial barrier (IEB) is also compromised by this inflammation. By emphasizing the central role of NLRP3 inflammasome activation in depression and its far-reaching implications, we go over each area with potential modulating mechanisms within the inflammasome pathway in hopes of finding new targets for more effective management of this debilitating condition.
抑郁症是全球残疾的最大促成因素，预计其数量还将持续增长。目前，既没有用于诊断该疾病的可靠生物标志物，现有的药物对近半数患者也不足以产生持久疗效。在这篇全面综述中，我们分析了该疾病先前已确立的病理生理模型，以及NLRP3炎性小体激活与抑郁症之间的相互作用如何能提供一个统一的视角。采用这一炎症理论，我们解释了NLRP3炎性小体激活如何成为抑郁炎症的关键促成因素，这一点得到了人体研究和动物模型的确凿证据支持。这种炎症存在于中枢神经系统（CNS）的神经元、星形胶质细胞和小胶质细胞中。值得注意的是，NLRP3炎性小体的失调超出了中枢神经系统的范围，渗透到肠道和外周免疫系统，从而改变微生物群-肠道-脑轴。这种炎症还会损害脑血屏障（BBB）和肠上皮屏障（IEB）的完整性。通过强调NLRP3炎性小体激活在抑郁症中的核心作用及其深远影响，我们探讨了炎性小体途径内每个具有潜在调节机制的领域，希望能找到新的靶点，以便更有效地治疗这种使人衰弱的疾病。
