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


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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    • "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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    • "Increased expression of CD4þ T cells Chiu et al. (2008) Saresella et al. (2013), Mantovani et al. (2009) Decreased expression of Tregs Zhao et al. (2012) (during rapidly progressing stage) Mantovani et al. (2009), Rentzos et al. (2012), Saresella et al. (2013) Complement activation Heurich et al. (2011), Lee et al. (2013), Woodruff et al. (2008) Ganesalingam et al. (2011), Sta et al. (2011), Woodruff et al. (2008) SOD1 in the CSF Miller et al. (2005), Ralph et al. (2005), Raoul et al. (2005) Winer et al. (2013) Increased neurofilament in blood/ CSF Boylan et al. (2009), Chen et al. (2014a), Lu et al. (2012) Boylan et al. (2013), Ganesalingam et al. (2011), Ganesalingam et al. (2013), Lehnert et al. (2014), Tortelli et al. (2012) T2 weighted MRI structural changes Evans et al. (2014), Marcuzzo et al. (2011) Vucic et al. (2008) Alterations in EIM Li et al. (2013), Wang et al. (2011) Rutkove et al. (2012), (2014) Alterations in MUNE Ngo et al. (2012), Shefner et al. (2006) Ahn et al. (2010), Armon and Brandstater (1999), Shefner et al. (2011) RAN dipeptide proteins Su et al. (2014) Su et al. (2014), Zu et al. (2013) b r a i n r e s e a r c h ] "
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