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      The immunology of stroke: from mechanisms to translation

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      Nature medicine

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          Abstract

          Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. While the immune system participates in the brain damage produced by ischemia, the damaged brain, in turn, exerts a powerful immunosuppressive effect that promotes fatal intercurrent infections and threatens the survival of stroke patients. Inflammatory signaling is instrumental in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion, to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke, like multiple sclerosis, engages both innate and adaptive immunity. But, unlike multiple sclerosis, adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. However, immunomodulation is not devoid of deleterious side effects, and gaining a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.

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          Most cited references 163

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          The inflammasomes.

          Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy. 2010 Elsevier Inc. All rights reserved.
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            Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo.

            Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells are highly active in their presumed resting state, continually surveying their microenvironment with extremely motile processes and protrusions. Furthermore, blood-brain barrier disruption provoked immediate and focal activation of microglia, switching their behavior from patroling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain.
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              Fate mapping analysis reveals that adult microglia derive from primitive macrophages.

              Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                16 May 2011
                07 July 2011
                07 January 2012
                : 17
                : 7
                : 796-808
                Affiliations
                Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065
                Author notes
                Correspondence: C. Iadecola, M.D., Division of Neurobiology, 407 East 61 th street; room 304, New York, NY 10065, Phone: 646/962-8279; Fax: 646/962-0535, coi2001@ 123456med.cornell.edu
                Article
                nihpa293758
                10.1038/nm.2399
                3137275
                21738161

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R37 NS034179-11 || NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R01 NS056456-05 || NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R01 NS035806-13 || NS
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                Medicine

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