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While astrocytes are heavily implicated in MS, little is known about their role in lesions, particularly in the lesion core. Here, we sought to gain insight into the spatial relationship between astrocytes and defined regions of chronic active lesions, and to better understand the environment within the relatively understudied lesion core, an area primarily composed of astrocytes. We analyzed four defined protein panels, focusing on astrocytes, in postmortem fresh-frozen cortical white matter tissue using NanoString GeoMx spatial protein profiling to compare normal appearing white matter (NAWM), the chronic active perilesion, rim, and core. We then performed immunofluorescent microscopy to determine the localization patterns of identified proteins within astrocytes. The most significant differences were observed between the chronic active lesion core and both NAWM and the perilesion. Proteins upregulated in the core relative to NAWM or the perilesion included the MAPK signaling pathway, immune checkpoint proteins, and indicators of phagocytosis. Our data indicate that astrocytes in the lesion core are distinct and actively influence the microenvironment. We posit that the differentially upregulated astrocytic signaling pathways, namely MAPK, immune checkpoints, and debris engulfment, are indicative of reactive astrocytes providing support to demyelinated axons by tempering the inflammatory milieu and clearing debris within the lesion core.<\/jats:p>","DOI":"10.1007\/s00401-025-02953-9","type":"journal-article","created":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T05:49:19Z","timestamp":1761976159000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Spatial protein profiling reveals active roles for astrocytes in the chronic active lesion core during multiple sclerosis"],"prefix":"10.1007","volume":"150","author":[{"given":"Brandon C.","family":"Smith","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Chomyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L.","family":"Habean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin C.","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A.","family":"Tinkey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Trapp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,1]]},"reference":[{"key":"2953_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41583-024-00823-z","volume":"25","author":"MS Woo","year":"2024","unstructured":"Woo MS, Engler JB, Friese MA (2024) The neuropathobiology of multiple sclerosis. 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