Novel insights into neuron-glia communication: the case of neuroinflammation triggered by the pesticide Maneb”

BENZI JUNCOS, O; CONDE, M.; ALZA, N.; SALVADOR, G. A.

Belem

Congreso; 3rd FALAN congress; 2022

3rd FALAN congress

FPR2/ALX signaling and their lipid mediator pathways: pleiotropic roles in neuroinflammation Benzi Juncos ON, Alza NP and Salvador GAInstituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB-UNS-CONICET)Maneb (MB) is a pesticide widely used for fungi plague control. Epidemiological studies have associated human prolonged exposure to MB with neurotoxicity and is considered an environmental risk factor for Parkinson’s disease. Little is yet known about the mechanisms underlying fungicide neurotoxicity and the involvement of the neuron-glia communication. Our aim was to elucidate the role of lipid dependent pathways associated with inflammation/resolution processes in neurons and glial cells challenged with MB.To elucidate possible alterations in neuron-glia crosstalk caused by MB toxicity, dopaminergic N27 cells were exposed to astrocyte (C6 cell line) secretome and vice versa. Astrocyte secretome showed to be neuroprotective against MB, while neurons secreted glial proliferative factors after pesticide exposure. COX-2 modulation by competitive and suicidal inhibitors did not alter the previously observed effect of secretomes. The pharmacological inhibition of LOX-15 and CYP450, both involved in the production of anti-inflammatory lipid mediators, abolished the glial proliferative effect of neuronal secretome during Mb toxicity in line with this the neuroprotective effect of astrocyte-derived secretome was blocked. Next, we evaluated the role of FPR2/ALX receptor, whose main ligands are lipid mediators associated with resolution. The antagonist of FPR2/ALX, Quin-C7 blocked the effect of the astrocyte secretome on neuronal survival upon MB challenge. To determine the role of FPR2/ALX downstream signaling, cells were exposed LY294002, and U0126 PI3K and Erk1/2 inhibitors respectively. Neuronal and astrocytic viability after MB exposure was independent of Erk1/2 activation, while the blockage of PI3K showed to enhance the damage caused by the pesticide. Moreover, Erk1/2 phosphorylation was diminished by MB in both cell types. Interestingly, we found that astrocyte response to neuronal secretome under pesticide toxicity was also mediated by Erk1/2 activation. Under this condition, the phosphorylation of Erk1/2 was increased, restoring control levels, and its inhibition reduced C6 proliferation.Our results suggest that FPR2/ALX signaling and their lipid ligands are involved in the neuronal-glia crosstalk during MB toxicity. These findings pay the way for interventions aimed at enhancing the resolution response during neuroinflammation events.