Mehterov Nikolay, Minchev Danail, Gevezova Maria, Sarafian Victoria, Maes Michael
Department of Medical Biology, Medical University of Plovdiv, Plovdiv, Bulgaria.
Research Institute at Medical University of Plovdiv, Plovdiv, Bulgaria.
Mol Neurobiol. 2022 Aug;59(8):4926-4952. doi: 10.1007/s12035-022-02889-1. Epub 2022 Jun 3.
The purpose of this review is to summarize the current knowledge regarding the reciprocal associations between brain-derived neurotrophic factor (BDNF) and immune-inflammatory pathways and how these links may explain the involvement of this neurotrophin in the immune pathophysiology of mood disorders and schizophrenia. Toward this end, we delineated the protein-protein interaction (PPI) network centered around BDNF and searched PubMed, Scopus, Google Scholar, and Science Direct for papers dealing with the involvement of BDNF in the major psychosis, neurodevelopment, neuronal functions, and immune-inflammatory and related pathways. The PPI network was built based on the significant interactions of BDNF with neurotrophic (NTRK2, NTF4, and NGFR), immune (cytokines, STAT3, TRAF6), and cell-cell junction (CTNNB, CDH1) DEPs (differentially expressed proteins). Enrichment analysis shows that the most significant terms associated with this PPI network are the tyrosine kinase receptor (TRKR) and Src homology region two domain-containing phosphatase-2 (SHP2) pathways, tyrosine kinase receptor signaling pathways, positive regulation of kinase and transferase activity, cytokine signaling, and negative regulation of the immune response. The participation of BDNF in the immune response and its interactions with neuroprotective and cell-cell adhesion DEPs is probably a conserved regulatory process which protects against the many detrimental effects of immune activation and hyperinflammation including neurotoxicity. Lowered BDNF levels in mood disorders and schizophrenia (a) are associated with disruptions in neurotrophic signaling and activated immune-inflammatory pathways leading to neurotoxicity and (b) may interact with the reduced expression of other DEPs (CTNNB1, CDH1, or DISC1) leading to multiple aberrations in synapse and axonal functions.
本综述的目的是总结目前关于脑源性神经营养因子（BDNF）与免疫炎症途径之间相互关系的知识，以及这些联系如何解释这种神经营养因子在情绪障碍和精神分裂症免疫病理生理学中的作用。为此，我们描绘了以BDNF为中心的蛋白质-蛋白质相互作用（PPI）网络，并在PubMed、Scopus、谷歌学术和科学Direct上搜索了有关BDNF参与主要精神病、神经发育、神经元功能以及免疫炎症和相关途径的论文。PPI网络是基于BDNF与神经营养因子（NTRK2、NTF4和NGFR）、免疫（细胞因子、STAT3、TRAF6）和细胞间连接（CTNNB、CDH1）差异表达蛋白（DEPs）的显著相互作用构建的。富集分析表明，与该PPI网络相关的最显著术语是酪氨酸激酶受体（TRKR）和含Src同源区2结构域的磷酸酶-2（SHP2）途径、酪氨酸激酶受体信号通路、激酶和转移酶活性的正调控、细胞因子信号传导以及免疫反应的负调控。BDNF参与免疫反应及其与神经保护和细胞间粘附DEPs的相互作用可能是一个保守的调节过程，可防止免疫激活和过度炎症的许多有害影响，包括神经毒性。情绪障碍和精神分裂症中BDNF水平降低（a）与神经营养信号传导中断和激活的免疫炎症途径导致神经毒性有关，（b）可能与其他DEPs（CTNNB1、CDH1或DISC1）表达降低相互作用，导致突触和轴突功能出现多种异常。
