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This challenge arises primarily due to an incomplete understanding of the dysregulated inflammatory and pro-resolving pathways underlying MS lesion progression. Bioactive lipid mediators (LMs), biosynthesized through the coordinated actions of specific enzymes like lipoxygenases (LOX) and cyclooxygenases (COX), are key regulators of both the initiation and resolution of an inflammatory response; however, their spatial organization and functional role during MS pathology have not been fully elucidated. Here, by using pneumatically assisted nanospray desorption electrospray ionization (PA nano-DESI) mass spectrometry imaging and immunohistochemistry, we reveal an increase in the LM leukotriene B\n                    <jats:sub>4<\/jats:sub>\n                    (LTB\n                    <jats:sub>4<\/jats:sub>\n                    ) in human MS white matter compared to controls, with further enrichment in MS lesions relative to perilesional areas, alongside elevated microglial 5-LOX activating protein (FLAP) expression. Pharmacological antagonism of FLAP suppresses LTB\n                    <jats:sub>4<\/jats:sub>\n                    biosynthesis in human-induced pluripotent stem cell (iPSC)-derived microglia with only marginal effects on the microglia transcriptional phenotype as determined by RNA sequencing. Moreover, in vivo FLAP antagonism ameliorates disease severity and spinal cord inflammatory gene expression in the experimental autoimmune encephalomyelitis (EAE) model, an animal model of MS, in both a prophylactic and therapeutic settings. This coincided with reduced local LTB\n                    <jats:sub>4<\/jats:sub>\n                    biosynthesis and reduced levels of inflammatory monocytes within the spinal cord during EAE. Together these findings establish the FLAP\/LTB\n                    <jats:sub>4<\/jats:sub>\n                    axis as a driver of neuroinflammation and a druggable therapeutic target for chronic inflammatory CNS disorders like MS.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03055-w","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T08:12:08Z","timestamp":1785831128000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microglial 5-LOX-activating protein antagonism alleviates leukotriene-driven neuroinflammation"],"prefix":"10.1007","volume":"152","author":[{"given":"Julia","family":"Konings","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fleur","family":"Mingneau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serhii","family":"Chornyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathrin E.","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne T. 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M. van der Brugt . Now, the author name has been corrected.","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2026","order":9,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":10,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":11,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1007\/s00401-026-03081-8","URL":"https:\/\/doi.org\/10.1007\/s00401-026-03081-8","order":12,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All donors or their next of kin provided fully informed consent for autopsy and use of material for research from the Netherlands Brain Bank under ethical approval by the Medical Ethics Committee of the Free University Medical Center in Amsterdam (2009\/148), project number 1,127. The generation of hiPSC from an NNC was approved by the LUMC Scientific Ethical Committee and informed consent was obtained (NL45478.058.13\/P13.080). All animal experiments were performed according to institutional guidelines and were approved by the Ethical Committee for Animal Experiments of Hasselt University under ethical matrix number ID202426.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":3,"name":"Ethics","label":"Consent for this publication","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"16"}}