{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:03:36Z","timestamp":1787169816983,"version":"build-2736575974"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in health and disease maintaining homeostasis and mediating neuroinflammatory responses. Their activation is a dynamic and context-dependent process characterized by diverse phenotypic states defined by transcriptomic, proteomic, and morphological characteristics. While lipopolysaccharide (LPS) is widely used as an inflammatory stimulus in microglial research, its physiological relevance remains debated. Interferon gamma (IFN\u03b3), a key pro-inflammatory cytokine involved in immune priming, more closely mimics CNS inflammatory conditions. In this study, we systematically investigated the temporal activation profiles of human iPSC-derived microglia (hiMG) in response to LPS, IFN\u03b3, and their combination. Transcriptomic analysis at 24\u202fh revealed robust differential gene expression, with over 7,000 genes altered by LPS and more than 8,500 by LPS\/IFN\u03b3 co-stimulation. These profiles partially overlapped with disease-associated microglia (DAM) signatures, including upregulation of\n                    <jats:italic>S100A9<\/jats:italic>\n                    ,\n                    <jats:italic>CD44<\/jats:italic>\n                    ,\n                    <jats:italic>ACSL1<\/jats:italic>\n                    , and\n                    <jats:italic>HIF1A<\/jats:italic>\n                    , and downregulation of\n                    <jats:italic>TREM2<\/jats:italic>\n                    ,\n                    <jats:italic>GPNMB<\/jats:italic>\n                    ,\n                    <jats:italic>FABP3<\/jats:italic>\n                    ,\n                    <jats:italic>LGMN<\/jats:italic>\n                    , and\n                    <jats:italic>LPL<\/jats:italic>\n                    . Cytokine expression changes were detectable as early as 1\u202fh post-treatment, predominantly following LPS exposure, and displayed distinct early (\u22642\u202fh), mid (4\u201312\u202fh), and late (24\u201396\u202fh) temporal patterns. IFN\u03b3 alone induced modest transcriptomic and cytokine responses but contributed to sustained inflammatory signatures when combined with LPS. Morphological analysis showed marked LPS- and LPS\/IFN\u03b3-induced structural remodeling of hiMG consistent with activation. To assess protein-level dynamics, targeted mass spectrometry quantified secreted ApoE, CD44, FUCA1, Galectin-3, and Osteopontin, all relevant to microglial activation, which were compared to cellular protein expression measured by western blot. Time-dependent increases were most prominent following LPS and LPS\/IFN\u03b3 treatment, although secreted Osteopontin levels were highest with IFN\u03b3 alone, highlighting stimulus-specific effects. Collectively, these data demonstrate that microglial activation is highly time- and stimulus-dependent, with LPS eliciting the strongest responses, and IFN\u03b3 modulating these effects. Our findings underscore the importance of temporal resolution in modeling microglial activation and provide insight into the mechanistic underpinnings of microglial activation relevant to neurodegeneration and therapeutic targeting.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2026.1756410","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T06:41:08Z","timestamp":1769668868000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The temporal and stimuli-specific effects of LPS and IFN\u03b3 on microglial activation"],"prefix":"10.3389","volume":"18","author":[{"given":"Christina N.","family":"Heiss","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S.","family":"Naylor","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Pes\u00e4maa","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arketa","family":"Meshi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"C\u00e9spedes-Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg","place":["Gothenburg, Sweden"]},{"name":"Laboratory of Stem Cells and Developmental Biology, Faculty of Science, University of Chile Santiago","place":["Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chim\u00e9ne","family":"Loun\u00e8s","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayat","family":"Taki","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina T\u00fcrner","family":"Stenstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dzeneta","family":"Vizlin-Hodzic","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg","place":["Gothenburg, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg","place":["Gothenburg, Sweden"]},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital","place":["M\u00f6lndal, Sweden"]},{"name":"Department of Neurodegenerative Disease, UCL Institute of Neurology","place":["London, United Kingdom"]},{"name":"UK Dementia Research Institute at UCL","place":["London, United Kingdom"]},{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health","place":["Madison, WI, United States"]},{"name":"Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison","place":["Madison, WI, United States"]},{"name":"Centre for Brain Research, Indian Institute of Science","place":["Bangalore, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica","family":"Palma","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cells and Developmental 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