IGF2-reprogrammed macrophages ameliorate the inflammatory response and protects against the neurodegenerative and neuroinflammatory process in Parkinson`s disease models.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra , which causes motor deficits. The most common histopathological feature of PD is the presence of α-synuclein (α-syn) misfolding protein and neurotoxic accumulations which leads to neuronal loss. Additionally, the inflammatory response arises as a relevant factor engage in modulate the neurodegeneration process in PD. An increase of proinflammatory cytokines in the blood and brain samples has been reported in PD patients. Also, peripheral blood T cells recognized α-syn, triggering a chronic inflammation in the blood and brain tissue in PD. IGF2 signaling has been involved on cellular reprogramming of macrophages to anti-inflammatory phenotype by epigenetic changes. Moreover, recently a decrease of IGF2 levels was reported in blood samples from PD patients. Methods: The inflammatory response was analyzed by flow cytometry, and qPCR in PBMCs from Chilean PD patients and macrophages isolated from α-syn overexpression transgenic mouse (ASO). We evaluated the motor impairment, systemic inflammation, neurodegeneration, α-syn accumulation and microglial activation in ASO mice treated via intravenous with IGF2-reprogrammed macrophages (MIGF2). Results: We showed a significant increase of proinflammatory markers in PBMCs from PD patients. Also, IGF2 prevented the proinflammatory phenotype triggered by exposure to α-syn PFF in murine primary macrophages. Furthermore, MIGF2 treatment significant decrease the motor impairment, systemic inflammation, and reduce neurodegeneration, α-syn accumulation and microglial activation levels in Substancia Nigra brain region during disease progression in ASO mice. Conclusions: PBMCs from Chilean PD patients showed an increase in proinflammatory profile. Additionally, MIGF2 has a neuroprotective effect in-vitro and in-vivo PD model. MIGF2 prevents motor impairment, neurodegeneration, and inflammation in the brain tissue of ASO mice in different stages of disease progression, suggesting its further application as a possible treatment for PD patients.