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We observed that LPS increased immunoreactive TLR4 and key steroidogenic enzymes in cortical astrocytes of rats and investigated whether corticosteroids are produced and mediate astrocytic TLR4\u2010dependent innate immune responses. We found that LPS increased steroidogenic acute regulatory protein (StAR) and StAR\u2010dependent aldosterone production in purified astrocytes. Both increases were blocked by the TLR4 antagonist TAK242. LPS also increased 11\u03b2\u2010hydroxysteroid dehydrogenase type 1 (11\u03b2\u2010HSD1) and corticosterone production, and both were prevented by TAK242 and by siRNAs against 11\u03b2\u2010HSD1, StAR, or aldosterone synthase (CYP11B2). Knockdown of 11\u03b2\u2010HSD1, StAR, or CYP11B2 or blocking either mineralocorticoid receptors (MR) or glucocorticoid receptors (GR) prevented dephosphorylation of p\u2010Ser\n                    <jats:sup>9<\/jats:sup>\n                    GSK\u20103\u03b2, activation of NF\u2010\u03baB, and the GSK\u20103\u03b2\u2010dependent increases of C3, IL\u20101\u03b2, and TNF\u2010\u03b1 caused by LPS. Exogenous aldosterone mimicked the MR\u2010 and GSK\u20103\u03b2\u2010dependent pro\u2010inflammatory effects of LPS in astrocytes, but corticosterone did not. Supernatants from astrocytes treated with LPS reduced MAP2 and viability of cultured neurons except when astrocytic StAR or MR was inhibited. In adrenalectomized rats, intracerebroventricular injection of LPS increased astrocytic TLR4, StAR, CYP11B2, and 11\u03b2\u2010HSD1, NF\u2010\u03baB, C3 and IL\u20101\u03b2, decreased astrocytic p\u2010Ser\n                    <jats:sup>9<\/jats:sup>\n                    GSK\u20103\u03b2 in the cortex and was neurotoxic, except when spironolactone was co\u2010injected, consistent with the in\u00a0vitro results. LPS also activated NF\u2010\u03baB in some NeuN\n                    <jats:sup>+<\/jats:sup>\n                    and CD11b\n                    <jats:sup>+<\/jats:sup>\n                    cells in the cortex, and these effects were prevented by spironolactone. We conclude that intracrine aldosterone may be involved in the TLR4\u2010dependent innate immune responses of astrocytes and can trigger paracrine effects by activating astrocytic MR\/GSK\u20103\u03b2\/NF\u2010\u03baB signaling.\n                  <\/jats:p>","DOI":"10.1096\/fj.202301923rr","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T14:19:52Z","timestamp":1719584392000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Toll\u2010like receptor 4\u2010dependent innate immune responses are mediated by intracrine corticosteroids and activation of glycogen synthase kinase\u20103\u03b2 in astrocytes"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5792-9323","authenticated-orcid":false,"given":"Wenfang","family":"Lai","sequence":"first","affiliation":[{"name":"College of Pharmacology Fujian University of Traditional Chinese Medicine  Minhou 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