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      Cytokines and Chemokines at the Crossroads of Neuroinflammation, Neurodegeneration, and Neuropathic Pain

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          Abstract

          Cytokines and chemokines are proteins that coordinate the immune response throughout the body. The dysregulation of cytokines and chemokines is a central feature in the development of neuroinflammation, neurodegeneration, and demyelination both in the central and peripheral nervous systems and in conditions of neuropathic pain. Pathological states within the nervous system can lead to activation of microglia. The latter may mediate neuronal and glial cell injury and death through production of proinflammatory factors such as cytokines and chemokines. These then help to mobilize the adaptive immune response. Although inflammation may induce beneficial effects such as pathogen clearance and phagocytosis of apoptotic cells, uncontrolled inflammation can result in detrimental outcomes via the production of neurotoxic factors that exacerbate neurodegenerative pathology. In states of prolonged inflammation, continual activation and recruitment of effector cells can establish a feedback loop that perpetuates inflammation and ultimately results in neuronal injury. A critical balance between repair and proinflammatory factors determines the outcome of a neurodegenerative process. This review will focus on how cytokines and chemokines affect neuroinflammation and disease pathogenesis in bacterial meningitis and brain abscesses, Lyme neuroborreliosis, human immunodeficiency virus encephalitis, and neuropathic pain.

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          Interleukin-6, a Major Cytokine in the Central Nervous System

          Interleukin-6 (IL-6) is a cytokine originally identified almost 30 years ago as a B-cell differentiation factor, capable of inducing the maturation of B cells into antibody-producing cells. As with many other cytokines, it was soon realized that IL-6 was not a factor only involved in the immune response, but with many critical roles in major physiological systems including the nervous system. IL-6 is now known to participate in neurogenesis (influencing both neurons and glial cells), and in the response of mature neurons and glial cells in normal conditions and following a wide arrange of injury models. In many respects, IL-6 behaves in a neurotrophin-like fashion, and seemingly makes understandable why the cytokine family that it belongs to is known as neuropoietins. Its expression is affected in several of the main brain diseases, and animal models strongly suggest that IL-6 could have a role in the observed neuropathology and that therefore it is a clear target of strategic therapies.
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            Interactions between the immune and nervous systems in pain.

            Immune cells and glia interact with neurons to alter pain sensitivity and to mediate the transition from acute to chronic pain. In response to injury, resident immune cells are activated and blood-borne immune cells are recruited to the site of injury. Immune cells not only contribute to immune protection but also initiate the sensitization of peripheral nociceptors. Through the synthesis and release of inflammatory mediators and interactions with neurotransmitters and their receptors, the immune cells, glia and neurons form an integrated network that coordinates immune responses and modulates the excitability of pain pathways. The immune system also reduces sensitization by producing immune-derived analgesic and anti-inflammatory or proresolution agents. A greater understanding of the role of the immune system in pain processing and modulation reveals potential targets for analgesic drug development and new therapeutic opportunities for managing chronic pain.
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              Nociceptors are interleukin-1beta sensors.

              A cardinal feature of inflammation is heightened pain sensitivity at the site of the inflamed tissue. This results from the local release by immune and injured cells of nociceptor sensitizers, including prostaglandin E(2), bradykinin, and nerve growth factor, that reduce the threshold and increase the excitability of the peripheral terminals of nociceptors so that they now respond to innocuous stimuli: the phenomenon of peripheral sensitization. We show here that the proinflammatory cytokine interleukin-1beta (IL-1beta), in addition to producing inflammation and inducing synthesis of several nociceptor sensitizers, also rapidly and directly activates nociceptors to generate action potentials and induce pain hypersensitivity. IL-1beta acts in a p38 mitogen-activated protein kinase (p38 MAP kinase)-dependent manner, to increase the excitability of nociceptors by relieving resting slow inactivation of tetrodotoxin-resistant voltage-gated sodium channels and also enhances persistent TTX-resistant current near threshold. By acting as an IL-1beta sensor, nociceptors can directly signal the presence of ongoing tissue inflammation.
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                Author and article information

                Journal
                Mediators Inflamm
                Mediators Inflamm
                MI
                Mediators of Inflammation
                Hindawi Publishing Corporation
                0962-9351
                1466-1861
                2013
                12 August 2013
                : 2013
                : 480739
                Affiliations
                1Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, 18703 Three Rivers Road, Covington, LA 70433, USA
                2Division of Comparative Pathology, Tulane National Primate Research Center, Tulane University, 18703 Three Rivers Road, Covington, LA 70433, USA
                Author notes

                Academic Editor: Luc Vallières

                Author information
                http://orcid.org/0000-0003-3505-8862
                Article
                10.1155/2013/480739
                3753746
                23997430
                79eaaa0b-7d11-4f5e-b71b-ac4105c097b4
                Copyright © 2013 Geeta Ramesh et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 3 May 2013
                : 11 July 2013
                : 12 July 2013
                Funding
                Funded by: http://dx.doi.org/10.13039/100000002 National Institutes of Health
                Award ID: 51OD011104/P51RR000164
                Funded by: http://dx.doi.org/10.13039/100000065 National Institute of Neurological Disorders and Stroke
                Award ID: NS048952
                Funded by: http://dx.doi.org/10.13039/100000025 National Institute of Mental Health
                Award ID: MH077544
                Categories
                Review Article

                Immunology
                Immunology

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