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      Exacerbation of experimental autoimmune encephalomyelitis in prion protein (PrPc)-null mice: evidence for a critical role of the central nervous system

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          Abstract

          Background

          The cellular prion protein (PrPc) is a host-encoded glycoprotein whose transconformation into PrP scrapie (PrPSc) initiates prion diseases. The role of PrPc in health is still obscure, but many candidate functions have been attributed to the protein, both in the immune and the nervous systems. Recent data show that experimental autoimmune encephalomyelitis (EAE) is worsened in mice lacking PrPc. Disease exacerbation has been attributed to T cells that would differentiate into more aggressive effectors when deprived of PrPc. However, alternative interpretations such as reduced resistance of neurons to autoimmune insult and exacerbated gliosis leading to neuronal deficits were not considered.

          Method

          To better discriminate the contribution of immune cells versus neural cells, reciprocal bone marrow chimeras with differential expression of PrPc in the lymphoid or in the central nervous system (CNS) were generated. Mice were subsequently challenged with MOG 35-55 peptide and clinical disease as well as histopathology were compared in both groups. Furthermore, to test directly the T cell hypothesis, we compared the encephalitogenicity of adoptively transferred PrPc-deficient versus PrPc-sufficient, anti-MOG T cells.

          Results

          First, EAE exacerbation in PrPc-deficient mice was confirmed. Irradiation exacerbated EAE in all the chimeras and controls, but disease was more severe in mice with a PrPc-deleted CNS and a normal immune system than in the reciprocal construction. Moreover, there was no indication that anti-MOG responses were different in PrPc-sufficient and PrPc-deficient mice. Paradoxically, PrPc-deficient anti-MOG 2D2 T cells were less pathogenic than PrPc-expressing 2D2 T cells.

          Conclusions

          In view of the present data, it can be concluded that the origin of EAE exacerbation in PrPc-ablated mice resides in the absence of the prion protein in the CNS. Furthermore, the absence of PrPc on both neural and immune cells does not synergize for disease worsening. These conclusions highlight the critical role of PrPc in maintaining the integrity of the CNS in situations of stress, especially during a neuroinflammatory insult.

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          Most cited references61

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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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            Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions.

            Microglia are crucially important myeloid cells in the CNS and constitute the first immunological barrier against pathogens and environmental insults. The factors controlling microglia recruitment from the blood remain elusive and the direct circulating microglia precursor has not yet been identified in vivo. Using a panel of bone marrow chimeric and adoptive transfer experiments, we found that circulating Ly-6C(hi)CCR2(+) monocytes were preferentially recruited to the lesioned brain and differentiated into microglia. Notably, microglia engraftment in CNS pathologies, which are not associated with overt blood-brain barrier disruption, required previous conditioning of brain (for example, by direct tissue irradiation). Our results identify Ly-6C(hi)CCR2(+) monocytes as direct precursors of microglia in the adult brain and establish the importance of local factors in the adult CNS for microglia engraftment.
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              Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.

              PrPC is a host protein anchored to the outer surface of neurons and to a lesser extent of lymphocytes and other cells. The transmissible agent (prion) responsible for scrapie is believed to be a modified form of PrPC. Mice homozygous for disrupted PrP genes have been generated. Surprisingly, they develop and behave normally for at least seven months, and no immunological defects are apparent. It is now feasible to determine whether mice devoid of PrPC can propagate prions and are susceptible to scrapie pathogenesis.
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                Author and article information

                Journal
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central
                1742-2094
                2012
                26 January 2012
                : 9
                : 25
                Affiliations
                [1 ]INSERM, UMR S 938, Centre de Recherche Hôpital Saint-Antoine, Paris, France
                [2 ]UPMC - Pierre and Marie Curie University (Paris 6), Paris, France
                [3 ]Department of Neurological Sciences, University of Florence, Florence, Italy
                [4 ]INSERM, UMR S 1064, CHU Hôtel-Dieu, 30 Bd Jean Monnet, 44093 Nantes cedex, France
                [5 ]L'UNAM - L'Université Nantes Angers Le Mans, Nantes, France
                [6 ]CHU de Nantes, ITUN, Nantes, France
                Article
                1742-2094-9-25
                10.1186/1742-2094-9-25
                3305405
                22281016
                99a9b093-ab29-40fe-af6f-ee67a3bf6398
                Copyright ©2012 Gourdain et al; BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 October 2011
                : 26 January 2012
                Categories
                Research

                Neurosciences
                bone marrow chimera,experimental autoimmune encephalomyelitis,cellular prion protein,biological function of prnp gene,gene conservation,neurodegeneration,glial activation,neuroprotection,prp knock-out

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