L-tri-iodothyronine (3, 3', 5-triiodothyronine; T3) is an active form of the thyroid hormone (TH) essential for the development and function of the CNS. Though nongenomic effect of TH, its plasma membrane-bound receptor, and its signaling has been identified, precise function in each cell type of the CNS remained to be investigated. Clearance of cell debris and apoptotic cells by microglia phagocytosis is a critical step for the restoration of damaged neuron-glia networks. Here we report nongenomic effects of T3 on microglial functions. Exposure to T3 increased migration, membrane ruffling and phagocytosis of primary cultured mouse microglia. Injection of T3 together with stab wound attracted more microglia to the lesion site in vivo. Blocking TH transporters and receptors (TRs) or TRα-knock-out (KO) suppressed T3-induced microglial migration and morphological change. The T3-induced microglial migration or membrane ruffling was attenuated by inhibiting Gi /o -protein as well as NO synthase, and subsequent signaling such as phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK). Inhibitors for Na(+) /K(+) -ATPase, reverse mode of Na(+) /Ca(2+) exchanger (NCX), and small-conductance Ca(2+) -dependent K(+) (SK) channel also attenuated microglial migration or phagocytosis. Interestingly, T3-induced microglial migration, but not phagocytosis, was dependent on GABAA and GABAB receptors, though GABA itself did not affect migratory aptitude. Our results demonstrate that T3 modulates multiple functional responses of microglia via multiple complex mechanisms, which may contribute to physiological and/or pathophysiological functions of the CNS.

Monocytes play a key role in the development of immune response in bacterial infection, because of their phagocytic, antigen-presenting and secretory functions. There are three subpopulations of monocytes: “classical” CD14+CD16-, “intermediate” CD14+CD16+, and “nonclassical” CD14+dimCD16+. These monocyte subtypes have different phenotypes and functions. The ratio of appropriate subpopulations varies with development of the antibacterial response. The aim of the present research was to study phenotypes of the monocyte subpopulations in the patients with sepsis, and changes in the monocyte subpopulation ratio, depending on the presence of bacteria in circulating blood of the patients, as well as to estimate contribution of the monocyte subpopulations to the cytokine production. We observed 16 patients with sepsis (10 men and 6 women; mean age, 58±14 years, SOFA 9.4±2.1; a total of 44 blood samples) examined in dynamics. The control group included healthy adults (n = 23, 12 men and 11 women; mean age, 51±13 years). Laboratory studies included bacteriological cultures, determination of absolute and relative numbers of subpopulations of classical, intermediate and non-classical monocytes and their expression of HLA-DR and CD64, determination of IL-6, TNFα, IL-1β, IL-10 concentration in blood serum. Absolute number of monocytes was increased in the sepsis patients, the ratio of classical monocytes was also increased, like as relative and absolute numbers of  intermediate cells. Meanwhile, the subpopulation of non-classical monocytes did not change significantly. The monocyte subpopulation ratio depended on the presence of bacteria in blood, i.e., a higher proportion of intermediate cells was observed in the samples positive for bacteria in blood cultures. The ratio of subpopulations was restored after elimination of bacteria from the circulation. The expression density of LPS receptor (CD14), IgG receptors (CD16 and  CD64) was found to be increased, especially in the subpopulations of intermediate and nonclassical monocytes. In all subpopulations of monocytes, expression of HLA-DR is reduced, most notably in classical monocytes, least in intermediate cells. There was a significant increase in serum levels of IL-6, IL-1β, TNFα and IL-10 cytokines. Direct correlation between the absolute number of classical monocytes and IL-6 concentration was revealed, as well as intensity of multiple organ dysfunction. Increase in absolute amount of classical monocytes and IL-6 concentration might serve as an indirect criterion for evaluation of endothelial activation, an active producer of IL-6 and myeloid cell growth factors. A direct correlation between the percentage of CD14+CD16+ cells and IL-10 concentration in blood serum indicates to an important role of intermediate monocytes in IL-10 production. IL-10 suppresses the antigen-presenting function of intermediate cells, namely, expression of HLA-DR molecules, as suggested by inverse correlation between the IL-10 concentration and HLA-DR expression density on CD14+CD16+ cells. We have also determined an inverse correlation between the degree of multi-organ dysfunction  and relative amount of HLA-DR+ monocytes. The larger was a classical monocyte subpopulation, the more noticeable was a decrease of this index. The studies in ratios of monocyte subpopulations help to understand the mechanisms of antibacterial protection in sepsis. Monitoring of classical monocyte numbers and serum concentrations of IL-6 is necessary for a comprehensive assessment of inflammatory response in sepsis. Determination of HLADR expression on monocytes allows us to evaluate the intensity of immune suppression in critically ill patients.

Introduction. Patients with chronic herpes virus infection develop impaired IFN-α and IFN-γ products due to secondary immunodeficiency, which leads to impaired elimination of the intracellular virus and the development of chronic recurrent infection. It has been shown that IFN-γ is a potent immunoregulatory cytokine and has an antiviral effect. The aim of the study is to study the effect of Ingaron therapy on the dynamics of IFN-α and IFN-γ production and the clinical picture in patients with chronic Epstein-Barr virus infection (ChEBVI). Material and methods. 32 patients with ChEBVI were examined. The average age of patients was 35.06 ± 1.60 years. There were 22 women, 10 men. Serum IFN-α and IFN-γ, spontaneous and induced cytokine production in blood lymphocyte cultures were determined. As an inducer of IFN-α products, the Newcastle disease virus was used (obtained in the LA Tarasevich State Medical Institute, St. Petersburg) with an infectious titer of 8 lg EID / 0.2 ml in a volume of 8 μl per well, as an inducer of IFN-γ products, phytohemagglutinin (PanEco, Russia) was used at a dose of 10 µg / ml. The quantitative content of cytokines was determined in the serum and supernatant of a 24-hour whole blood culture using enzyme-linked immunosorbent assay (ELISA) using test systems (Vector Best, Russia). Results. It was shown that the content of IFN-γ decreased (P = 0.013) after Ingaron therapy in patients with initially high levels of induced IFN-γ (4435.64 ± 1343.50 pg/ml). In patients with initially low levels of induced IFN-γ (234.25 ± 34 , 31 pg / ml) the content of IFN-γ increased (P = 0.002). Ingaron leads to an increase in spontaneous and serum IFN-γ production in patients. Conclusions. Conducting Ingaron therapy with ChEBVI is shown independently of the initial production of IFN-γ-induced lymphocyte culture. Ingaron is recommended for the treatment of patients with ChEBVI at a dose of 500,000 IU with a course dose of 10 or more injections.

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