Microglia-specific IL-10 gene delivery inhibits neuroinflammation and neurodegeneration in a mouse model of Parkinson’s disease

Neuroinflammation plays a key role in modulating dopaminergic neuronal (DAN) cell loss in Parkinson’s disease (PD). However, it remains unresolved how to effectively normalize this immune response given the complex interplay between the innate and adaptive immune responses occurring within a scarcely accessible organ like the brain. In this study, we uncovered a consistent correlation between neuroinflammation, brain parenchymal lymphocytes and DAN cell loss among several commonly used mouse models of PD generated by a variety of pathological triggers. We validated a viral therapeutic approach for the microglia-specific expression of Interleukin 10 (IL-10) to selectively mitigate the excessive inflammatory response. We found that this approach induced a local nigral IL-10 release that sustained a robust neuroprotection against α-Synuclein (αSYN)-induced neurodegeneration. Single-cell transcriptomics revealed the emergence of a molecularly alternative microglial cell state specifically induced by IL-10 enriched in markers of cell activation with enhanced expression of prophagocytic pathways. Indeed, Il-10 strongly promoted phagocytotic and clearance activities that effectively reduced the αSYN aggregate burden in the nigral area. Furthermore, IL-10 stimulated the differentiation of CD4+ T lymphocytes into active T regulatory cells. Finally, CD8+ T cells exhibited enhanced inhibitory characteristics in the presence of IL-10. Thus, IL-10 local transduction elicited a strong immunomodulation in the nigral tissue with enhanced suppression of lymphocyte toxicity, which rescued DAN cell loss. These results offer insights into the therapeutic benefits induced by IL-10, showcasing a promising gene delivery approach that minimizes undesired side effects and has a strong translational relevance.