Activin-A Restrains Inflammatory Responses in the CNS and Ameliorates α-Synuclein Pathology in Parkinson's disease
M. Karampetsou1, M. Semitekolou2, E. Emmanouilidou1, I. Morianos2, E. Kapaki3, O. M.A. El-Agnaf 4, K.Vekrellis1* and G. Xanthou2* 1Dept. of Neuroscience, Biomedical Research Foundation of the Academy of Athens (BRFAA), Greece; 2Cell Immunology Lab, BRFAA, Greece; 3Neurology Dept., University of Athens, Athens, Greece; 4Neurological Disorders Center, Qatar Biomedical Research Institute and Khalifa University, Doha, Qatar *Corresponding authors
Recent genetic association studies link variability that underlies Parkinson's disease (PD) with gene expression changes in immune cells. While the cytokine activin-A exerts neuroprotective functions in several brain injury models, its role in a-syn-induced pathology and neurodegeneration remains elusive. Here, we administered recombinant activin-A (or neutralizing antibody) in A53T a-syn transgenic mice and in mice exposed to pre-formed a-syn fibrils (PFFs). Our findings reveal that activin-A is upregulated in neurons in the striatum and cortex of A53T-a-syn expressing and PFF-injected mice. Administration of activin-A increases Iba+ microglia cells to levels similar to WT controls and dampens TNF-α and IL-1β in the CNS and serum. Neutralization of activin-A exacerbates inflammatory responses in A53T mice, as shown by increases in the recruitment of CD45highCD11b+CCR2+ myeloid cells in the cortex and striatum. Importantly, activin-A decreases pathological phospho-a-syn accumulations in the midbrain in PFF-injected mice. These strong neuroprotective effects of activin-A are associated with increased GFAP+ astrocytes and decreased recruitment of CD45+CD11b+Ly6C+ myeloid cells and draining lymph nodes (DLNs). The percentages of CD4+Foxp3+ regulatory T cells are also elevated in the DLNs. Notably in both PD models, activin-A greatly enhances IL-10 in the CNS and the periphery. Expression profiles in cortical neurons isolated from PFF-treated, activin-A-administered mice, reveal that activin-A, among other genes, regulates the expression of aryl hydrocarbon receptor and its target gene, CYPA1, supporting a role for AhR in activin-A-induced IL-10 gene regulation. Finally, activin-A is significantly decreased in the CSF and serum of PD patients. Collectively, these findings uncover activin-A as a crucial protective cytokine that may be exploited as a novel therapeutic target for halting PD progression.
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