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After brain injury, astrocytes become reactive, and that involves a profound change in the astroglial gene expression program as well as intense cytoskeleton remodeling that has been classically shown by the up\u2010regulation of glial fibrillary acidic protein (GFAP), a pan\u2010reactive gene over\u2010expressed in reactive astrocytes, independently of the type of injury. Using the stab wound rodent model of penetrating traumatic injury in the cortex, we here studied the reactive astroglial morphology and reactive microgliosis in detail at 1, 3, 7, 14, and 28\u2009days post\u2010injury (dpi). By combining immunohistochemistry, morphometrical parameters, and Sholl analysis, we segmented the astroglial cell population into clusters of reactive astrocytes that were localized in the core, penumbra, and distal regions of the stab wound. Specifically, highly reactive clusters with more complex morphology, increased C3, decreased aquaporin\u20104 (AQP4), and glutamine synthetase (GS) expression, were enriched at 7 dpi when behavioral alterations, microgliosis, and neuronal alterations in injured mice were most significant. While pro\u2010inflammatory gain of function with peripheral lipopolysaccharide (LPS) administration immediately after a stab wound expanded these highly reactive astroglial clusters, the treatment with the NF\u2010\u03baB inhibitor sulfasalazine reduced the abundance of this highly reactive cluster. Increased neuronal loss and exacerbated reactive microgliosis at 7 dpi were associated with the expansion of the highly reactive astroglial cluster. We conclude that highly reactive astrocytes found in stab wound injury, but expanded in pro\u2010inflammatory conditions, are a population of astrocytes that become engaged in pathological remodeling with a pro\u2010inflammatory gain of function and loss of homeostatic capacity. Controlling this astroglial population may be a tempting strategy to reduce neuronal loss and neuroinflammation in the injured brain.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15941-fig-0012-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.15941","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T15:34:16Z","timestamp":1692632056000},"page":"183-203","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Progression of reactive gliosis and astroglial phenotypic changes following stab wound\u2010induced traumatic brain injury in mice"],"prefix":"10.1111","volume":"167","author":[{"given":"Maria Belen","family":"Cieri","sequence":"first","affiliation":[{"name":"Laboratorio de Neuropatolog\u00eda Molecular, Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. De Robertis\u201d, UBA\u2010CONICET, Facultad de Medicina Universidad de Buenos Aires  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Villarreal","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuropatolog\u00eda Molecular, Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. De Robertis\u201d, UBA\u2010CONICET, Facultad de Medicina Universidad de Buenos Aires  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dante Daniel","family":"Gomez\u2010Cuautle","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuropatolog\u00eda Molecular, Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. De Robertis\u201d, UBA\u2010CONICET, Facultad de Medicina Universidad de Buenos Aires  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Mailing","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuropatolog\u00eda Molecular, Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. De Robertis\u201d, UBA\u2010CONICET, Facultad de Medicina Universidad de Buenos Aires  Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4009-6337","authenticated-orcid":false,"given":"Alberto Javier","family":"Ramos","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuropatolog\u00eda Molecular, Instituto de Biolog\u00eda Celular y Neurociencia \u201cProf. E. 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