Benzi_2025_Cell.Mol.Life.Sci_82_327

Environmental toxicants such as maneb (MB), a dithiocarbamate pesticide, trigger progressive neuronal death, probably due to the imbalance in inflammation/resolution mechanisms, resulting in the onset of neurodegeneration. The inflammation/resolution balance is governed by G protein-coupled receptor (GPCR) signaling, but it has been poorly described in the Central Nervous System (CNS), since resolution GPCR ligands are negligible and elusive lipid compounds. These mediators are mainly synthesized by lipoxygenases (ALOX) from arachidonic acid (AA) and docosahexaenoic acid (DHA) released by specific phospholipases A2 (PLA2). Thus, we aimed to characterize the molecular components of resolution involved in neuron-astrocyte communication in response to MB-induced toxicity. The metabolomics study showed significant changes in 20 metabolites in neurons and 43 in astrocytes as a response to MB treatment. Major phospholipids' content (phosphatidylcholine - PC - and phosphatidylethanolamine) was reduced in both cell types with a simultaneous increase in lysophospholipids. In silico analysis revealed the upregulation of a Group IID secretory phospholipase A2 (sPLA2-IID), and the fatty acid profile showed increased neuronal DHA content and decreased AA and DHA levels in astrocytes. In addition, increased DHA esterified-PC content in neurons exposed to MB was observed. Astrocyte secretome and its lipid extract protected neurons against MB-induced toxicity. This neuroprotective effect was abolished by blocking AA and DHA oxygenation by ALOX-15 and associated with the activation of the formyl peptide receptor 2 (FPR2/ALX), probably mediated by lipoxin A4. Moreover, a neuronal lipid ligand induced astrocyte proliferation through this GPCR. Our study suggests that molecular components of the FPR2/ALX pathway participate in both the neuroprotection exerted by astrocytes and astrocytic proliferative signals shaped by neurons under MB toxicity.