Article

F.108. T Lymphocytes Potentiate Endogenous Neuroprotective Inflammation in a Mouse Model of ALS

Department of Pathology, Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2008; 105(46):17913-8. DOI: 10.1073/pnas.0804610105
Source: PubMed

ABSTRACT

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease, in which the role of inflammation is not well established. Innate and adaptive immunity were investigated in the CNS of the Superoxide Dismutase 1 (SOD1)(G93A) transgenic mouse model of ALS. CD4+ and CD8+ T cells infiltrated SOD1(G93A) spinal cords during disease progression. Cell-specific flow cytometry and gene expression profiling showed significant phenotypic changes in microglia, including dendritic cell receptor acquisition, and expression of genes linked to neuroprotection, cholesterol metabolism and tissue remodeling. Microglia dramatically up-regulated IGF-1 and down-regulated IL-6 expression. When mutant SOD1 mice were bred onto a TCRbeta deficient background, disease progression was significantly accelerated at the symptomatic stage. In addition, microglia reactivity and IGF-1 levels were reduced in spinal cords of SOD1(G93A) (TCRbeta-/-) mice. These results indicate that T cells play an endogenous neuroprotective role in ALS by modulating a beneficial inflammatory response to neuronal injury.

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    • "The infiltration of lymphocytes within the CNS parenchyma is a common hallmark in many pathological conditions (RezaiZadeh et al., 2009;Anderson et al., 2014) such as VIH (Petito et al., 2003) and West Nile virus infection (Glass et al., 2005); neurodegenerative diseases such as Parkinson's disease (Brochard et al., 2009) and amyotrophic lateral sclerosis (Holmoy, 2008); acute lesions like facial nerve axotomy (Raivich et al., 1998), entorhinal cortex lesion (Babcock et al., 2008), stroke (Schroeter et al., 1994;Gelderblom et al., 2009) and ischemia (Gelderblom et al., 2009) or autoimmune processes such as experimental autoimmune encephalomyelitis (Dittel, 2008;Almolda et al., 2011a). While in some circumstances lymphocyte infiltration has been related to protective functions, as occurs in the facial nerve axotomy paradigm (Serpe et al., 1999), the West Nile virus infection (Glass et al., 2005) and amyotrophic lateral sclerosis (Beers et al., 2008;Chiu et al., 2008), in other circumstances lymphocyte infiltration has been shown to contribute to the exacerbation of the pathology. This is the case of Parkinson's disease (Brochard et al., 2009), VIH virus infection (Petito et al., 2003), stroke (Yilmaz et al., 2006) and some autoimmune diseases (Dittel, 2008). "
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    ABSTRACT: The infiltration of immune cells in the central nervous system is a common hallmark in different neuroinflammatory conditions. Accumulating evidence indicates that resident glial cells can establish a cross-talk with infiltrated immune cells, including T-cells, regulating their recruitment, activation and function within the CNS. Although the healthy CNS has been thought to be devoid of professional dendritic cells (DCs), numerous studies have reported the presence of a population of DCs in specific locations such as the meninges, choroid plexuses and the perivascular space. Moreover, the infiltration of DC precursors during neuroinflammatory situations has been proposed, suggesting a putative role of these cells in the regulation of lymphocyte activity within the CNS. On the other hand, under specific circumstances, microglial cells are able to acquire a phenotype of DC expressing a wide range of molecules that equip these cells with all the necessary machinery for communication with T-cells. In this review, we summarize the current knowledge on the expression of molecules involved in the cross-talk with T-cells in both microglial cells and DCs and discuss the potential contribution of each of these cell populations on the control of lymphocyte function within the CNS.
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    • "Moreover, by QPCR, we showed that TNFα-treatment increases miR-125b levels in microglia, thus creating a vicious cycle possibly culminating in abnormal TNFα release. Given that IL-6, a marker of activated microglia, is reported to be down regulated after symptom onset in ALS animal models [127] and that TNFα is up regulated in G93A mice and in ALS patients [128] [129] [130], our results indicate that miR-365 and miR-125b dysregulations might condition the pathological cytokine profile of ALS [126]. "

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    • "They get properties of antigen-presenting cells and start to interact with T-cells, which infiltrate in the affected spinal cord and cortex (Alexianu et al., 2001; Engelhardt et al., 1993). This microglial activation starts shortly before disease onset and the number of activated glia and infiltrated T-cells increases with disease progression (Alexianu et al., 2001; Beers et al., 2008; Chiu et al., 2008; Gowing et al., 2008; Hall et al., 1998). The functional alterations that accompany these inflammatory events could contribute to motor neuron death. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterized by the selective death of motor neurons in the motor cortex, brainstem and spinal cord. It is a neurodegenerative disorder with high genetic and phenotypic variability. In most patients, the cause of the disease is unknown. Until now, no treatment strategy has been discovered with the exception of riluzole which has a moderate effect on the disease process. While developing a new causal therapy targeting a specific disease-causing gene can have a huge effect on the disease process, only a limited number of ALS patients will benefit from such a therapy. Alternatively, pathogenic processes that are common in ALS patients with different etiology can also be targeted. The effect of such a modifying treatment will be smaller, but the target population will be larger as more ALS patients could benefit. In this review, we summarize the evidence for the involvement of different biological processes in the pathogenesis of ALS and will discuss how strategies influencing these processes can be translated into new therapeutic approaches. In order to further improve this translational step, there is an urgent need for a better understanding of the underlying mechanism(s), for new ALS animal models and for rigorous protocols to perform preclinical studies.
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