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Transforming growth factor beta1 (TGF-\u03b21) is widely recognized as an anti-inflammatory cytokine, which can be produced by both glial and neuronal cells in CNS. However, the effects of TGF-\u03b21 on demyelinating diseases and its underlying mechanisms have not been well investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A demyelinating mouse model using two-point injection of lysophosphatidylcholine (LPC) to the corpus callosum in vivo was established. Exogenous TGF-\u03b21 was delivered to the lesion via brain stereotactic injection. LFB staining, immunofluorescence, and Western blot were applied to examine the severity of demyelination and pyroptosis process in microglia. Morris water maze test was used to assess the cognitive abilities of experimental mice. Furthermore, lipopolysaccharide (LPS) was applied to induce pyroptosis in primary cultured microglia in vitro, to explore potential molecular mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The degree of demyelination in LPC-modeling mice was found improved with supplement of TGF-\u03b21. Besides, TGF-\u03b21 treatment evidently ameliorated the activated proinflammatory pyroptosis of microglia, with downregulated levels of the key pyroptosis effector Gasdermin D (GSDMD), inflammasomes, and cleaved-IL-1\u03b2, which effectively attenuated neuroinflammation in vivo. Evaluated by behavioral tests, the cognitive deficit in LPC-modeling mice was found mitigated with application of TGF-\u03b21. Mechanistically, TGF-\u03b21 could reverse pyroptosis-like morphology in LPS-stimulated primary cultured microglia observed by scanning electron microscopy, as well as decrease the protein levels of cleaved-GSDMD, inflammasomes, and cleaved-IL-1\u03b2. Activation of ERK1\/2 and NF-\u03baB pathways largely abolished the protective effects of TGF-\u03b21, which indicated that TGF-\u03b21 alleviated the pyroptosis possibly via regulating NF-\u03baB\/ERK1\/2 signal pathways.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our studies demonstrated TGF-\u03b21 notably relieved the demyelinating injury and cognitive disorder in LPC-modeling mice, by attenuating the inflammatory pyroptosis of microglia via ERK1\/2 and NF-\u03baB pathways. Targeting TGF-\u03b21 activity might serve as a promising therapeutic strategy in demyelinating diseases.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12974-022-02557-0","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T13:02:39Z","timestamp":1659013359000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Transforming growth factor-\u03b21 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-\u03baB\/ERK1\/2 pathways"],"prefix":"10.1186","volume":"19","author":[{"given":"Yi","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simiao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,28]]},"reference":[{"key":"2557_CR1","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.jaut.2014.01.022","volume":"48\u201349","author":"D Karussis","year":"2014","unstructured":"Karussis D. 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