Glatiramer Acetate Modulates TNF-α and IL-10 Secretion in Microglia and Promotes Their Phagocytic Activity

Pul, Refik; Moharregh-Khiabani, Darius; Škuljec, Jelena; Skripuletz, Thomas; Garde, Niklas; Voß, Elke; Stangel, Martin

doi:10.1007/s11481-010-9248-1

Cited by 59 publications

(46 citation statements)

References 41 publications

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“…Recently, we demonstrated that GA drives microglia to adopt a type II APC similar to monocytes and DCs suggesting a general effect on myelo-monocytic cells [16]. We additionally discovered that GA directly and distinctly increases phagocytic activity of primary rat microglia.…”

Section: Introductionmentioning

confidence: 79%

Glatiramer Acetate Increases Phagocytic Activity of Human Monocytes In Vitro and in Multiple Sclerosis Patients

et al. 2012

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Beside its effects on T cells, a direct influence on cells of the myelo-monocytic lineage by GA becomes evident. Recently, we demonstrated that GA drives microglia to adopt properties of type II antigen presenting cells (APC) and increases their phagocytic activity. In the present work, we focused on human blood monocytes in order to examine whether GA may increase phagocytic activity in vivo and to evaluate the molecular mechanisms explaining this new discovered mode of action. Peripheral blood mononuclear cells (PBMC) were obtained using a Biocoll-Isopaque gradient and monocytes were subsequently isolated by using CD14 MicroBeads. Phagocytic activity was determined by flow cytometric measurement of the ingestion of fluorescent beads. Flow cytometry was also used to assess monocytic differentiation and expression of phagocytic receptors. Monocytes of GA treated MS patients exhibited a significantly higher phagocytic activity than those of healthy controls or non-treated MS patients. In vitro, a significant phagocytic response was already detectable after 1 h of GA treatment at the concentrations of 62.5 and 125 µg/ml. A significant increase at all concentrations of GA was observed after 3 h and 24 h, respectively. Only monocytes co-expressing CD16, particularly CD14++CD16+ cells, were observed to phagocytose. Treatment of monocytes with IL-10 and supernatants from GA-treated monocytes did not alter phagocytosis. We observed a decrease in CD11c expression by GA while no changes were found in the expression of CD11b, CD36, CD51/61, CD91, TIM-3, and CD206. In our blocking assays, treatment with anti-CD14, anti-CD16, anti-TIM3, anti-CD210, and particularly anti-CD36 antibodies led to a decrease in phagocytosis. Our results demonstrate a new mechanism of action of GA treatment that augments phagocytic activity of human monocytes in vivo and in vitro. This activity seems to arise from the CD14++CD16+ monocyte subset.

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Section: Introductionmentioning

confidence: 79%

Glatiramer Acetate Increases Phagocytic Activity of Human Monocytes In Vitro and in Multiple Sclerosis Patients

et al. 2012

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“…Since microglia have been recognized as an important contributor to tissue damage and disease progression in MS [10], it is possible that part of the beneficial effect of glatiramer acetate in MS is derived from an effect on microglia. Indeed, glatiramer acetate has been found to have direct effects on microglia, promoting differentiation of monocytes and microglia into antigen-presenting cells [28] and stimulating phagocytosis by microglia in vitro [29]. …”

Section: Discussionmentioning

confidence: 99%

Decreased microglial activation in MS patients treated with glatiramer acetate

et al. 2011

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Activated microglia are thought to be an important contributor to tissue damage in multiple sclerosis (MS). The level of microglial activation can be measured non-invasively using [11C]-R-PK11195, a radiopharmaceutical for positron emission tomography (PET). Prior studies have identified abnormalities in the level of [11C]-R-PK11195 uptake in patients with MS, but treatment effects have not been evaluated. Nine previously untreated relapsing-remitting MS patients underwent PET and magnetic resonance imaging (MRI) of the brain at baseline and after one year of treatment with glatiramer acetate. Parametric maps of [11C]-R-PK11195 uptake were obtained for baseline and post-treatment PET scans, and the change in [11C]-R-PK11195 uptake pre- to post-treatment was evaluated across the whole brain. Region of interest analysis was also applied to selected subregions. Whole brain [11C]-R-PK11195 binding potential per unit volume decreased 3.17% (95% CI: −0.74%, −5.53%) between baseline and one year (p = 0.018). A significant decrease was noted in cortical gray matter and cerebral white matter, and a trend towards decreased uptake was seen in the putamen and thalamus. The results are consistent with a reduction in inflammation due to treatment with glatiramer acetate, though a larger controlled study would be required to prove that association. Future research will focus on whether the level of baseline microglial activation predicts future tissue damage in MS and whether [11C]-R-PK11195 uptake in cortical gray matter correlates with cortical lesion load.

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“…The production of IL-10 by microglia can also be induced in a PRR-independent manner. Glatiramer acetate, an immunomodulatory agent used in relapsing-remitting multiple sclerosis, was shown to induce secretion of IL-10 by microglial cells [95]. Resveratrol administration to a microglial cell line prevented hypoxia-induced injury by up-regulating IL-10 and controlling inflammation [96].…”

Section: Cellular Sources Of Il-10 In the Cnsmentioning

confidence: 99%

Balancing the immune response in the brain: IL-10 and its regulation

Lobo-Silva

Carriche

Castro

et al. 2016

J Neuroinflammation

327

199

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BackgroundThe inflammatory response is critical to fight insults, such as pathogen invasion or tissue damage, but if not resolved often becomes detrimental to the host. A growing body of evidence places non-resolved inflammation at the core of various pathologies, from cancer to neurodegenerative diseases. It is therefore not surprising that the immune system has evolved several regulatory mechanisms to achieve maximum protection in the absence of pathology.Main bodyThe production of the anti-inflammatory cytokine interleukin (IL)-10 is one of the most important mechanisms evolved by many immune cells to counteract damage driven by excessive inflammation. Innate immune cells of the central nervous system, notably microglia, are no exception and produce IL-10 downstream of pattern recognition receptors activation. However, whereas the molecular mechanisms regulating IL-10 expression by innate and acquired immune cells of the periphery have been extensively addressed, our knowledge on the modulation of IL-10 expression by central nervous cells is much scattered. This review addresses the current understanding on the molecular mechanisms regulating IL-10 expression by innate immune cells of the brain and the implications of IL-10 modulation in neurodegenerative disorders.ConclusionThe regulation of IL-10 production by central nervous cells remains a challenging field. Answering the many remaining outstanding questions will contribute to the design of targeted approaches aiming at controlling deleterious inflammation in the brain.

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Glatiramer Acetate Modulates TNF-α and IL-10 Secretion in Microglia and Promotes Their Phagocytic Activity

Cited by 59 publications

References 41 publications

Glatiramer Acetate Increases Phagocytic Activity of Human Monocytes In Vitro and in Multiple Sclerosis Patients

Glatiramer Acetate Increases Phagocytic Activity of Human Monocytes In Vitro and in Multiple Sclerosis Patients

Decreased microglial activation in MS patients treated with glatiramer acetate

Balancing the immune response in the brain: IL-10 and its regulation

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