{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:42:00Z","timestamp":1790779320377,"version":"4.1.0"},"reference-count":61,"publisher":"American Society for Clinical Investigation","issue":"1","license":[{"start":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01AG083943"],"award-info":[{"award-number":["R01AG083943"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32100787"],"award-info":[{"award-number":["32100787"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82271377"],"award-info":[{"award-number":["82271377"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:p>Neuromyelitis optica (NMO) is an autoimmune disorder characterized by autoantibodies against the astrocyte water channel aquaporin-4 (AQP4) that cause demyelination in the optic nerves and spinal cord. How astrocytopathy leads to myelination deficits remains unclear. Chitinase-3\u2013like protein 1 (CHI3L1, also known as YKL-40) is predominantly secreted by activated astrocytes, serves as a robust NMO biomarker, and plays a role in immune responses, but how it is induced and shapes astrocyte activation in NMO is not well defined. Using ex vivo and in vivo NMO mouse models together with mice with astrocyte-specific CHI3L1 knockout, we demonstrated that CHI3L1 directly contributed to demyelinating lesions elicited by AQP4 autoantibody\u2013activated astrocytes. With complementary in vitro assays and inducible transgenic lines, we uncovered an astrocyte-intrinsic cascade in which AQP4 autoantibody exposure activated STAT3, which in turn drove CHI3L1 expression and secretion. Secreted CHI3L1 then engaged the astrocytic receptor RAGE in an autocrine manner, activating downstream NF-\u03baB signaling that drove proinflammatory gliosis and damaged myelination. Pharmacological blockade of this pathway in NMO models rescued demyelinating pathology and improved motor function. These findings reveal an astrocyte-intrinsic CHI3L1 pathway that contributed to demyelination in NMO and identify actionable therapeutic targets.<\/jats:p>","DOI":"10.1172\/jci195506","type":"journal-article","created":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T19:01:04Z","timestamp":1767294064000},"source":"Crossref","is-referenced-by-count":4,"title":["Astrocyte-intrinsic signaling of chitinase-like protein CHI3L1 drives inflammation and amplifies demyelination in neuromyelitis optica"],"prefix":"10.1172","volume":"136","author":[{"given":"Huiming","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Neurology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 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