NF-κB/mTOR/MYC Axis Drives PRMT5 Protein Induction After T Cell Activation via Transcriptional and Non-transcriptional Mechanisms

Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) mediated by CD4+ T cells and modeled via experimental autoimmune encephalomyelitis (EAE). Inhibition of PRMT5, the major Type II arginine methyltransferase, suppresses pathogenic T cell responses and EAE. PRMT5 is transiently induced in proliferating memory inflammatory Th1 cells and during EAE. However, the mechanisms driving PRMT5 protein induction and repression as T cells expand and return to resting is currently unknown. Here, we used naive mouse and memory mouse and human Th1/Th2 cells as models to identify mechanisms controlling PRMT5 protein expression in initial and recall T cell activation. Initial activation of naive mouse T cells resulted in NF-κB-dependent transient Prmt5 transcription and NF-κB, mTOR and MYC-dependent PRMT5 protein induction. In murine memory Th cells, transcription and miRNA loss supported PRMT5 induction to a lesser extent than in naive T cells. In contrast, NF-κB/MYC/mTOR-dependent non-transcriptional PRMT5 induction played a major role. These results highlight the importance of the NF-κB/mTOR/MYC axis in PRMT5-driven pathogenic T cell expansion and may guide targeted therapeutic strategies for MS

CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions

Macrophages and their monocyte precursors mediate innate immune responses and can promote a spectrum of phenotypes from pro-inflammatory to pro-resolving. Currently, there are few markers that allow for robust dissection of macrophage phenotype. We recently identified CD38 as a marker of inflammatory macrophages in murine in vitro and in vivo models. However, it is unknown whether CD38 plays a similar marker and/or functional role in human macrophages and inflammatory diseases. Here, we establish that CD38 transcript and protein are robustly induced in human macrophages exposed to LPS (±IFN-γ) inflammatory stimuli, but not with the alternative stimulus, IL-4. Pharmacologic and/or genetic CD38 loss-of-function significantly reduced the secretion of inflammatory cytokines IL-6 and IL-12p40 and glycolytic activity in human primary macrophages. Finally, monocyte analyses in systemic lupus erythematosus patients revealed that, while all monocytes express CD38, high CD38 expression in the non-classical monocyte subpopulation is associated with disease. These data are consistent with an inflammatory marker role for CD38 in human macrophages and monocytes

The Effectiveness of Bobath’s Method in the Correction of Psychophysical Condition of Preschool Age Children with Cerebral Palsy

Стаття присвячена проблемі застосування методу Бобат як основної методики корекції психофізичного стану дітей дошкільного віку з ДЦП. Основою експерименту стала оцінка формування елементарних рухових навичок в основних вихідних положеннях на початку й динаміка оволодівання ними наприкінці курсу проведення корекційних розвиваючих занять методом Бобат у дітей дошкільного віку з ДЦП. У результаті було визначено, що за час курсу застосування методу Бобат, істотно покращилися показники оволодівання елементарними руховими навичками.This article deals with the problem of determining the effectiveness of the Bobath’s method as the main correction of the psychophysical condition method of preschool age children with cerebral palsy. In a modern application of correction the measures are directed on the recovery of motor and psycho-emotional realms to the problem of choosing and applying the most effective techniques contribute to the normalization of motor activity of children with central nervous system involvement. Critical to the success of the correction of psychophysical children’s condition are adequate control over the effective use of the individual techniques in the course of application the Bobath’s method course. In the literature there is a wide variety of the tests to assess motor ability, however, they are difficult to use and functional. Therefore, the improvement of the existing tests and the introduction of new scales of assessment to improve the effectiveness correction of motor disorders are extremely urgent. This article deals with the problem of determining the effectiveness of the Bobath’s method as the main method correction psychomotor development. In the literature there is a wide variety of tests to assess motor abilities, however, they are difficult to use and functional. In our assessing the effectiveness of the remedial practice of the Bobath’s method with «Card-test the motor ability of children from 3 months to adulthood», which efficiently defines the stages of motor development of the child. Due to its universality, accessibility and informativeness of this test it has become possible to qualitatively assess of the stages of psychomotor development of children with cerebral palsy. The basis experiment was an evaluation of the formation of elementary motor skills at the beginning and the dynamics of handling them at the end of the course of Bobath’s therapy lessons with preschool children with cerebral palsy. At the end of the experiment it was determined that during the Bobath’s method course elementary motor skills in initial positions such as: lying on the back and abdomen, standing on all fours had significant improvement. It should be noted that the marked improvement is determined by mastery of the basic elementary motor skills, which testify the effectiveness of the method of Bobath in the correction of psychophysical prеschool age children with cerebral palsy

image_3_CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions.TIF

<p>Macrophages and their monocyte precursors mediate innate immune responses and can promote a spectrum of phenotypes from pro-inflammatory to pro-resolving. Currently, there are few markers that allow for robust dissection of macrophage phenotype. We recently identified CD38 as a marker of inflammatory macrophages in murine in vitro and in vivo models. However, it is unknown whether CD38 plays a similar marker and/or functional role in human macrophages and inflammatory diseases. Here, we establish that CD38 transcript and protein are robustly induced in human macrophages exposed to LPS (±IFN-γ) inflammatory stimuli, but not with the alternative stimulus, IL-4. Pharmacologic and/or genetic CD38 loss-of-function significantly reduced the secretion of inflammatory cytokines IL-6 and IL-12p40 and glycolytic activity in human primary macrophages. Finally, monocyte analyses in systemic lupus erythematosus patients revealed that, while all monocytes express CD38, high CD38 expression in the non-classical monocyte subpopulation is associated with disease. These data are consistent with an inflammatory marker role for CD38 in human macrophages and monocytes.</p

image_1_CD38 Is Robustly Induced in Human Macrophages and Monocytes in Inflammatory Conditions.TIF

<p>Macrophages and their monocyte precursors mediate innate immune responses and can promote a spectrum of phenotypes from pro-inflammatory to pro-resolving. Currently, there are few markers that allow for robust dissection of macrophage phenotype. We recently identified CD38 as a marker of inflammatory macrophages in murine in vitro and in vivo models. However, it is unknown whether CD38 plays a similar marker and/or functional role in human macrophages and inflammatory diseases. Here, we establish that CD38 transcript and protein are robustly induced in human macrophages exposed to LPS (±IFN-γ) inflammatory stimuli, but not with the alternative stimulus, IL-4. Pharmacologic and/or genetic CD38 loss-of-function significantly reduced the secretion of inflammatory cytokines IL-6 and IL-12p40 and glycolytic activity in human primary macrophages. Finally, monocyte analyses in systemic lupus erythematosus patients revealed that, while all monocytes express CD38, high CD38 expression in the non-classical monocyte subpopulation is associated with disease. These data are consistent with an inflammatory marker role for CD38 in human macrophages and monocytes.</p