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Bioactive lipid mediators (LMs) derived from polyunsaturated fatty acids (PUFAs) are key molecules in both the initiation and resolution of inflammatory responses. Previous findings suggest that a dysregulated LM balance, especially within the arachidonic acid (AA) pathway, may contribute to an impaired resolution response and subsequent chronic neuroinflammation in multiple sclerosis (MS). However, to date, the local biosynthesis and signaling of LMs within the brain of people with MS (PwMS) remains unexplored. In this study, we, therefore, mapped the distribution of AA and its key downstream LM prostaglandin E₂ (PGE₂) in white matter MS brain tissue and of non-neurological controls (NNCs) for the first time using mass spectrometry imaging. We found that AA levels are lower in MS cases compared to NNCs and reduced in MS lesions compared to peri-lesional tissue. Furthermore, the PGE₂/AA ratio, indicating the PGE₂ synthesis from the AA substrate, was increased in lesion areas compared to fully myelinated regions in MS. In line with that, the expression of prostaglandin synthesizing enzymes as measured by RT-qPCR was partially increased in MS tissue compared to NNCs. In addition, the expression of prostaglandin E2 receptor 4 (EP4) decreased, while prostaglandin E2 receptor 2 (EP2) showed increased expression levels in MS lesions compared to NNCs and localized specifically to microglia. We also found that PGE₂ addition to pro-inflammatory human-induced pluripotent stem cell (iPSC)-derived microglia resulted in enhanced cytokine signaling pathways, but also the upregulation of its synthase PTGES and homeostatic/resolving signaling, the latter of which might mainly occur through EP2 signaling. Collectively, our results provide detailed information about the region-specific levels of AA and PGE₂ in MS lesions and we propose enhanced PGE₂-EP2 signaling in inflamed microglia in MS.