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A hallmark of PD is the presence of misfolded \u03b1\u2010synuclein (\u03b1\u2010syn) proteins and their neurotoxic accumulations, contributing to neuronal loss. Additionally, the inflammatory response plays a critical role in modulating the neurodegeneration process in PD. Moreover, peripheral macrophages recognize \u03b1\u2010syn, triggering chronic inflammation in both the bloodstream and brain tissue, leading to elevated levels of proinflammatory cytokines, as it was observed in PD patient samples. Insulin\u2010like growth factor 2 (IGF2) is a secreted factor with neuroprotective properties in several neurodegenerative disease models. Moreover, IGF2 signaling has been implicated in the cellular reprogramming of macrophages to an anti\u2010inflammatory phenotype through epigenetic changes. Recently, reduced IGF2 levels in both plasma and peripheral blood mononuclear cells (PBMCs) from PD patient samples were reported, suggesting a potential link between IGF2 levels and inflammation. In this study, we investigated the inflammatory profile of PD patients and the effect of IGF2\u2010reprogrammed macrophages in in\u00a0vitro and in\u00a0vivo PD models. Here, we report a significant increase in proinflammatory markers in PBMCs from PD patients. IGF2 treatment prevented \u03b1\u2010syn\u2010induced pro\u2010inflammatory profile in murine primary macrophages. Notably, IGF2\u2010reprogrammed macrophage treatment significantly reduced motor impairment, \u03b1\u2010syn accumulation, and microglial activation in the\n                    <jats:italic>Substantia Nigra<\/jats:italic>\n                    across different stages of disease progression in the PD preclinical model. These findings highlight the immunomodulatory effect of IGF2 on macrophages and its potential therapeutic impact on PD.\n                  <\/jats:p>","DOI":"10.1111\/acel.70020","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T06:15:11Z","timestamp":1743315311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["<scp>IGF2<\/scp>\n                    \u2010Reprogrammed Macrophages Ameliorate the Inflammatory Response and Protect Against the Neuroinflammatory Process in Parkinson's Disease Models"],"prefix":"10.1111","volume":"24","author":[{"given":"Felipe","family":"Grunenwald","sequence":"first","affiliation":[{"name":"Center for Integrative Biology Universidad Mayor  Santiago Chile"},{"name":"Biomedical Neuroscience Institute University of Chile  Santiago Chile"},{"name":"Center for Geroscience, Brain Health and Metabolism  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas J.","family":"Huerta","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology Universidad Mayor  Santiago Chile"},{"name":"Biomedical Neuroscience Institute University of Chile  Santiago Chile"},{"name":"Center for Geroscience, Brain Health and Metabolism  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denisse","family":"Sepulveda","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology Universidad Mayor  Santiago Chile"},{"name":"Biomedical Neuroscience Institute University of Chile  Santiago Chile"},{"name":"Center for Geroscience, Brain Health and Metabolism  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Jerez","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology Universidad Mayor  Santiago Chile"},{"name":"Biomedical Neuroscience Institute University of Chile  Santiago Chile"},{"name":"Center for Geroscience, Brain Health and Metabolism  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Urbina","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology Universidad Mayor  Santiago Chile"},{"name":"Biomedical Neuroscience Institute University of Chile  Santiago Chile"},{"name":"Center for Geroscience, Brain Health and Metabolism  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e1rbara","family":"Carrera","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology Universidad Mayor  Santiago Chile"},{"name":"Biomedical Neuroscience Institute University of Chile  Santiago Chile"},{"name":"Center for Geroscience, Brain Health and Metabolism  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Diaz\u2010Espinoza","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda, Facultad de Qu\u00edmica y Biolog\u00eda Universidad de Santiago de Chile  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esteban","family":"Nova","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, Facultad de Ciencias Naturales, Matem\u00e1ticas y Medio Ambiente Universidad Tecnol\u00f3gica Metropolitana  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Pacheco","sequence":"additional","affiliation":[{"name":"Fundacion Ciencia &amp; 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