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
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.