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

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          Abstract

          Background

          The 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 body

          The 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.

          Conclusion

          The 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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          Most cited references88

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          Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

          Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.
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            Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones

            A cytokine synthesis inhibitory factor (CSIF) is secreted by Th2 clones in response to Con A or antigen stimulation, but is absent in supernatants from Con A-induced Th1 clones. CSIF can inhibit the production of IL-2, IL-3, lymphotoxin (LT)/TNF, IFN-gamma, and granulocyte-macrophage CSF (GM-CSF) by Th1 cells responding to antigen and APC, but Th2 cytokine synthesis is not significantly affected. Transforming growth factor beta (TGF-beta) also inhibits IFN-gamma production, although less effectively than CSIF, whereas IL-2 and IL-4 partially antagonize the activity of CSIF. CSIF inhibition of cytokine synthesis is not complete, since early cytokine synthesis (before 8 h) is not significantly affected, whereas later synthesis is strongly inhibited. In the presence of CSIF, IFN-gamma mRNA levels are reduced slightly at 8, and strongly at 12 h after stimulation. Inhibition of cytokine expression by CSIF is not due to a general reduction in Th1 cell viability, since actin mRNA levels were not reduced, and proliferation of antigen-stimulated cells in response to IL-2, was unaffected. Biochemical characterization, mAbs, and recombinant or purified cytokines showed that CSIF is distinct from IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IFN-gamma, GM-CSF, TGF-beta, TNF, LT, and P40. The potential role of CSIF in crossregulation of Th1 and Th2 responses is discussed.
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              Microglia: Dynamic Mediators of Synapse Development and Plasticity.

              Neuronal communication underlies all brain activity and the genesis of complex behavior. Emerging research has revealed an unexpected role for immune molecules in the development and plasticity of neuronal synapses. Moreover microglia, the resident immune cells of the brain, express and secrete immune-related signaling molecules that alter synaptic transmission and plasticity in the absence of inflammation. When inflammation does occur, microglia modify synaptic connections and synaptic plasticity required for learning and memory. Here we review recent findings demonstrating how the dynamic interactions between neurons and microglia shape the circuitry of the nervous system in the healthy brain and how altered neuron-microglia signaling could contribute to disease.
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                Author and article information

                Contributors
                diogosilva@med.uminho.pt
                guilherminamc@gmail.com
                acastro@med.uminho.pt
                sroque@med.uminho.pt
                margarida.saraiva@ibmc.up.pt
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                24 November 2016
                24 November 2016
                2016
                : 13
                : 297
                Affiliations
                [1 ]Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
                [2 ]ICVS/3B’s PT Government Associate Laboratory, Braga, Portugal
                [3 ]i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
                [4 ]IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
                Author information
                http://orcid.org/0000-0002-8180-1293
                Article
                763
                10.1186/s12974-016-0763-8
                5121946
                27881137
                41b41631-5b26-4182-929b-072a3b639fd7
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 21 September 2016
                : 11 November 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;
                Award ID: SFRH/BD/88081/2012
                Award ID: SFRH/BPD/72710/2010
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2016

                Neurosciences
                interleukin-10,pattern recognition receptors,glial cells,molecular regulation,neurodegeneration

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