Abstract
Neurodegenerative diseases, characterised by the progressive and selective neuronal death in the central nervous system, are frequently accompanied by an activated immune system. In Huntington’s disease (HD), clinical and animal studies show evidence of immune activity, along with hyper-reactive monocyte/macrophage responses, while application of immunosuppressive regimens have imparted beneficial effects to HD mice. These findings suggest a contributory role of the immune system in HD pathology, with immune-based interventions offering a potential therapeutic strategy. Herein, we show that peripheral and CNS immune system activity increased with disease progression in HD mouse models and defined the phenotype of the immune response. Additionally, the depletion of monocytes and macrophages in vivo, via clodronate liposome treatment, revealed a major contributory role of these innate immune cells to the chronic inflammatory milieu observed during the course of the disease. This suggests that peripheral immunomodulatory strategies targeting monocytes and macrophages could be relevant for HD.
Highlights
The contribution of the immune system to the pathology of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD) has gathered increasing interest and momentum with the ultimate hope of finding effective immune-based therapeutic strategies[1,2,3,4,5]
We have shown that the cells that promote immune hyperactivation during disease progression in HD mouse models are macrophages and monocytes, as inferred by previous studies, and T cells and dendritic cell (DC)
We characterised the macrophage response in HD according to the M1 and M2 phenotypic classification, and found that this differed depending on the tissue in which these cells reside
Summary
The contribution of the immune system to the pathology of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD) has gathered increasing interest and momentum with the ultimate hope of finding effective immune-based therapeutic strategies[1,2,3,4,5]. The major component of the central nervous system (CNS) immunity, have long been observed to be activated in presymptomatic HD10, more recent results suggest a role for the peripheral immune system in HD progression. This has taken the form of elevated levels of plasma cytokines[9] and chemokines[11] such as IL6 and TNFα in HD mouse models and patients, along with dysregulated monocyte and macrophage in vitro responses[9,12,13]. We used clodronate liposomes[23,24] to selectively deplete phagocytic monocyte/macrophage and DC populations from blood and tissues, resulting in cytokine normalisation, and demonstrating that macrophages contribute to the in vivo chronic inflammatory milieu that we observed in R6/2 mice from an early symptomatic stage of disease
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