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A promising target to enhance remyelination is the immunomodulatory cytokine tumor necrosis factor alpha (TNF\u03b1) and its receptors TNFR1 and TNFR2. TNFR2 on oligodendrocyte lineage cells and microglia coordinates different protective functions, such as proliferation of oligodendrocyte progenitor cells, survival of mature oligodendrocytes, and release of anti-inflammatory cytokines, in animal models of inflammation and demyelination. Here, we find in the cuprizone model that following demyelination, fewer axons are unmyelinated in the corpus callosum at an early stage of remyelination after single TNFR2 agonist delivery in the lateral ventricle, while astrocyte and microglia number and coverage are unchanged. Towards later stages of remyelination, TNFR2 agonist treatment maintains the number of oligodendrocyte lineage cells, and large caliber axons have thinner myelin. Hence, even short-term stimulation of TNFR2 has a positive impact on the remyelination processes. This study informs further on the beneficial implications of TNFR2 signaling on oligodendrocyte lineage cells and remyelination, emphasizing its potential therapeutic value for demyelinating diseases, including multiple sclerosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key messages<\/jats:title>\n                    <jats:p>\n                      Single TNFR2 agonist treatment in the lateral ventricle following cuprizone-induced demyelination impacts remyelination by:\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Leading to a lower percentage of unmyelinated axons at early stages.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Preserving the number of oligodendrocyte lineage cells in the corpus callosum at later stages.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Covering large calibre axons with thinner myelin sheaths at later stages.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00109-025-02549-6","type":"journal-article","created":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T03:21:35Z","timestamp":1746847295000},"page":"795-807","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Single intracerebroventricular TNFR2 agonist injection impacts remyelination in the cuprizone model"],"prefix":"10.1007","volume":"103","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1148-4541","authenticated-orcid":false,"given":"Valentina","family":"Pegoretti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4771-5156","authenticated-orcid":false,"given":"Ate","family":"Boerema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5300-2139","authenticated-orcid":false,"given":"Kim","family":"Kats","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8410-6407","authenticated-orcid":false,"given":"Juan M.","family":"Dafauce Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7927-604X","authenticated-orcid":false,"given":"Roman","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7139-1350","authenticated-orcid":false,"given":"Roland E.","family":"Kontermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3441-9227","authenticated-orcid":false,"given":"Klaus","family":"Pfizenmaier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5085-9807","authenticated-orcid":false,"given":"Jon D.","family":"Laman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4178-0384","authenticated-orcid":false,"given":"Ulrich L. 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