Spatial mapping of the AA-PGE₂-EP axis in multiple sclerosis lesions.

Area of Science:

• Neuroinflammation research
• Lipid mediator biochemistry
• Multiple Sclerosis pathogenesis

Background:

• Bioactive lipid mediators (LMs) from polyunsaturated fatty acids (PUFAs) regulate inflammation.
• An imbalanced LM profile, particularly from the arachidonic acid (AA) pathway, is implicated in chronic neuroinflammation in Multiple Sclerosis (MS).
• Local LM biosynthesis and signaling in the MS brain remain understudied.

Purpose of the Study:

• To map the distribution of arachidonic acid (AA) and prostaglandin E2 (PGE2) in MS brain tissue.
• To investigate the relationship between AA, PGE2, and their synthesizing enzymes and receptors in MS lesions.
• To explore the functional role of PGE2 in microglia within the context of MS.

Main Methods:

• Mass spectrometry imaging of AA and PGE2 in MS and non-neurological control (NNC) brain tissue.
• RT-qPCR to measure prostaglandin synthesizing enzyme expression.
• Immunohistochemistry to assess receptor expression (EP2, EP4) and cell localization.
• In vitro studies using induced pluripotent stem cell (iPSC)-derived microglia exposed to PGE2.

Main Results:

• AA levels were lower in MS cases and reduced in MS lesions compared to peri-lesional tissue.
• The PGE2/AA ratio was elevated in MS lesions, indicating increased PGE2 synthesis.
• Prostaglandin synthesizing enzyme expression was partially increased in MS tissue.
• Prostaglandin E2 receptor 4 (EP4) expression decreased, while EP2 expression increased in MS lesions, with EP2 localized to microglia.
• PGE2 treatment of iPSC-derived microglia enhanced pro-inflammatory cytokine pathways and upregulated its synthase (PTGES), while also activating homeostatic/resolving signaling, potentially via EP2.

Conclusions:

• This study provides the first detailed regional analysis of AA and PGE2 in MS brain lesions.
• Results suggest enhanced PGE2 synthesis and signaling, particularly through the EP2 receptor on microglia, in inflamed MS lesions.
• These findings highlight a potential role for PGE2-EP2 signaling in the complex inflammatory and resolving processes within the MS brain.