{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:51:04Z","timestamp":1792792264750,"version":"4.5.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T00:00:00Z","timestamp":1720137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012032","name":"Fondazione Romeo Ed Enrica Invernizzi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012032","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Abnormal spreading of alpha-synuclein (\u03b1S), a hallmark of Parkinson\u2019s disease, is known to promote peripheral inflammation, which occurs in part via functional alterations in monocytes\/macrophages. However, underlying intracellular mechanisms remain unclear.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Herein we investigate the subcellular, molecular, and functional effects of excess \u03b1S in human THP-1 monocytic cell line, THP-1-derived macrophages, and at least preliminarily, in primary monocyte-derived macrophages (MDMs). In cells cultured w\/wo recombinant \u03b1S (1\u00a0\u03bcM) for 4\u00a0h and 24\u00a0h, by Confocal microscopy, Western Blot, RT-qPCR, Elisa, and Flow Cytometry we assessed: i) \u03b1S internalization; ii) cytokine\/chemokine expression\/secretion, and C\u2013C motif chemokine receptor 2 (CCR2) levels; iii) autophagy (LC3II\/I, LAMP1\/LysoTracker, p62, pS6\/total S6); and iv) lipid droplets (LDs) accumulation, and cholesterol pathway gene expression. Transwell migration assay was employed to measure THP-1 cell migration\/chemotaxis, while FITC-IgG-bead assay was used to analyze phagocytic capacity, and the fate of phagocytosed cargo in THP-1-derived macrophages.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Extracellular \u03b1S was internalized by THP-1 cells, THP-1-derived macrophages, and MDMs. In THP1 cells, \u03b1S induced a general pro-inflammatory profile and conditioned media from \u03b1S-exposed THP-1 cells potently attracted unstimulated cells. However, CCL2 secretion peaked at 4\u00a0h \u03b1S, consistent with early internalization of its receptor CCR2, while this was blunted at 24\u00a0h \u03b1S exposure, when CCR2 recycled back to the plasma membrane. Again, 4\u00a0h \u03b1S-exposed THP-1 cells showed increased spontaneous migration, while 24\u00a0h \u03b1S-exposed cells showed reduced chemotaxis. This occurred in the absence of cell toxicity and was associated with upregulation of autophagy\/lysosomal markers, suggesting a pro-survival\/tolerance mechanism against stress-related inflammation. Instead, in THP-1-derived macrophages, \u03b1S time-dependently potentiated the intracellular accumulation, and release of pro-inflammatory mediators. This was accompanied by mild toxicity, reduced autophagy-lysosomal markers, defective LDs formation, as well as impaired phagocytosis, and the appearance of stagnant lysosomes engulfed with phagocytosed cargo, suggesting a status of macrophage exhaustion reminiscent of hypophagia.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> In summary, despite an apparently similar pro-inflammatory phenotype, monocytes and macrophages respond differently to intracellular \u03b1S accumulation in terms of cell survival, metabolism, and functions. Our results suggest that in periphery, \u03b1S exerts cell- and context-specific biological effects bridging alterations of autophagy, lipid dynamics, and inflammatory pathways.<\/jats:p>","DOI":"10.3389\/fcell.2024.1421360","type":"journal-article","created":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T05:15:59Z","timestamp":1720156559000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Alpha-synuclein shapes monocyte and macrophage cell biology and functions by bridging alterations of autophagy and inflammatory pathways"],"prefix":"10.3389","volume":"12","author":[{"given":"Fiona","family":"Limanaqi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Zecchini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Ogno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Artusa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Fenizia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irma","family":"Saulle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Vanetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela","family":"Garziano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Strizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Trabattoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Clerici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Biasin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"110090","DOI":"10.1016\/j.celrep.2021.110090","article-title":"Alpha synuclein, the culprit in Parkinson disease, is required for normal immune function","volume":"38","author":"Alam","year":"2022","journal-title":"Cell Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3233\/JPD-140491","article-title":"Role of \u03b1-synuclein in inducing innate and adaptive immunity in Parkinson disease","volume":"5","author":"Allen Reish","year":"2015","journal-title":"J. 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