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No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the lack of therapies aimed at promoting remyelination and slowing disease progression for individuals with MS. Here, we found that the protein kinase C (PKC)\u2013modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, shifts the transcriptional programs of microglia and CNS-associated macrophages from a proinflammatory phenotype to a regenerative phenotype in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevented the activation of neuroinflammatory reactive astrocytes while also promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment of mice with bryo-1 augmented remyelination after a focal demyelinating injury. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin-regenerative and supportive agents in MS and other neurologic diseases.<\/jats:p>","DOI":"10.1126\/scitranslmed.adk3434","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T18:58:20Z","timestamp":1736362700000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":13,"title":["The protein kinase C modulator bryostatin-1 therapeutically targets microglia to attenuate neuroinflammation and promote remyelination"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4546-0890","authenticated-orcid":true,"given":"Payam","family":"Gharibani","sequence":"first","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8677-4028","authenticated-orcid":true,"given":"Efrat","family":"Abramson","sequence":"additional","affiliation":[{"name":"Interdepartmental Neuroscience Program, Yale University School of Medicine, Yale University, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5659-2250","authenticated-orcid":true,"given":"Shruthi","family":"Shanmukha","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6614-569X","authenticated-orcid":true,"given":"Matthew D.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley H.","family":"Godfrey","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9862-3502","authenticated-orcid":true,"given":"Judy J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8789-3013","authenticated-orcid":true,"given":"Jingwen","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."},{"name":"Department of Biology, Georgetown University, Washington, DC 20057, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5310-2383","authenticated-orcid":true,"given":"Maryna","family":"Baydyuk","sequence":"additional","affiliation":[{"name":"Department of Biology, Georgetown University, Washington, DC 20057, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1285-6087","authenticated-orcid":true,"given":"Marie-France","family":"Dorion","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6802-0708","authenticated-orcid":true,"given":"Yu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1627-5186","authenticated-orcid":true,"given":"Andrew J.","family":"Calle","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6240-106X","authenticated-orcid":true,"given":"Soonmyung","family":"A. 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