Guryanova Svetlana V, Kataeva Anastasiya
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of Russian Academy of Sciences, Ministry of Science and Higher Education of the Russian Federation, 117997 Moscow, Russia.
Medical Institute, Peoples' Friendship University of Russia (RUDN University) of the Ministry of Science and Higher Education of the Russian Federation, 117198 Moscow, Russia.
Biomedicines. 2023 Jan 11;11(1):183. doi: 10.3390/biomedicines11010183.
Stimulation of innate immunity by bacterial molecular patterns can induce an enhanced cellular immune response to pathogens that are associated with innate immune memory shaped by epigenetic changes. Immunological memory can be expressed in the acceleration/intensification of inflammation, as well as in the exact opposite-to maintain tolerance and non-response to a repeated stimulus. Tolerance is one of the central concepts of immunity and is ensured by the consistency of all parts of the immune response. The severe consequences of inflammation force researchers to study in detail all stages of the downstream pathways that are activated after exposure to a stimulus, while the formation of non-response to a pro-inflammatory stimulus has not yet received a detailed description. Elucidation of the mechanism of tolerance is an urgent task for the prevention and treatment of inflammatory diseases. The aim of this investigation was to study the dynamic changes in the gene expression of A20 and ATF3, the inflammation suppressors, against the background of the expression of the genes of the innate immunity receptors TLR4 and NOD2 and the pro-inflammatory cytokine TNF-α under the influence of TLR4 and NOD2 agonists, lipopolysaccharide (LPS) and glucosaminylmuramyl dipeptide (GMDP). The mechanism of inflammation regulation by bioregulators of bacterial origin-LPS and GMDP-was evaluated in vitro in human peripheral blood mononuclear cells and in vivo after i.p. administration of LPS and GMDP to mice. Gene expression was assessed by RT-PCR. Innate immune receptors and the pro-inflammatory cytokine TNF-α were found to develop early in response to LPS and GMDP, both in vitro and in vivo. Genes of cytosolic proteins controlling inflammation (A20 and ATF3) were expressed later. Prior exposure of the innate immune system to LPS and muramyl peptides may modulate host defense against acute inflammation. As a result of the study, new data were obtained on dynamic changes in deubiquitinase A20 and the transcription factor ATF3, which are involved in the limitation and suppression of inflammatory reactions caused by fragments of bacterial cell walls-LPS and GMDP. Thus, bioregulators of bacterial origin LPS and GMDP, along with pro-inflammatory factors, activate the expression of genes that suppress inflammation, which should be considered when analyzing data from studies of the pro-inflammatory properties of LPS and GMDP and when developing drugs based on them.
细菌分子模式对先天免疫的刺激可诱导对病原体的细胞免疫反应增强，这种反应与由表观遗传变化塑造的先天免疫记忆相关。免疫记忆可表现为炎症的加速/强化，也可表现为完全相反的情况——维持对重复刺激的耐受性和无反应性。耐受性是免疫的核心概念之一，由免疫反应各部分的一致性来确保。炎症的严重后果促使研究人员详细研究接触刺激后激活的下游通路的所有阶段，而对促炎刺激无反应的形成尚未得到详细描述。阐明耐受性机制是预防和治疗炎症性疾病的紧迫任务。本研究的目的是在先天免疫受体TLR4和NOD2以及促炎细胞因子TNF-α基因表达的背景下，研究炎症抑制因子A20和ATF3基因表达的动态变化，这些变化受TLR4和NOD2激动剂脂多糖（LPS）和氨基葡糖胞壁酰二肽（GMDP）的影响。在体外人外周血单核细胞中以及在给小鼠腹腔注射LPS和GMDP后在体内评估了细菌来源的生物调节剂LPS和GMDP对炎症的调节机制。通过RT-PCR评估基因表达。发现先天免疫受体和促炎细胞因子TNF-α在体外和体内对LPS和GMDP的反应中早期就会产生变化。控制炎症的胞质蛋白（A20和ATF3）基因稍后表达。先天免疫系统预先接触LPS和胞壁酰肽可能会调节宿主对急性炎症的防御。作为研究结果，获得了关于去泛素化酶A20和转录因子ATF3动态变化的新数据它们参与限制和抑制由细菌细胞壁片段LPS和GMDP引起的炎症反应。因此，细菌来源的生物调节剂LPS和GMDP与促炎因子一起激活抑制炎症的基因表达，在分析LPS和GMDP促炎特性的研究数据以及基于它们开发药物时应考虑到这一点。
