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Neopterin, a well-established biomarker for immune system activation, is found at increased levels in the cerebrospinal fluid of individuals affected by neurological/neurodegenerative diseases. Here, neopterin synthesis was investigated in different nerve cells (rodent and human) and in the mouse hippocampus under inflammatory stimuli. We also aimed to investigate whether neopterin preconditioning could modulate the inflammasome activation, a component of the innate immune system. Increased neopterin was detected in human nerve cells supernatants (highest secretion in astrocytes) exposed to lipopolysaccharide (LPS) and interferon-gamma (INF-γ) and in the hippocampus of mice receiving LPS (0.33 mg/kg; intraperitoneal). In parallel to the hippocampal-increased neopterin, it was observed a significant increase in the expression of the rate-limiting enzyme of its biosynthetic pathway, and both phenomena occurred before the inflammasome activation. Moreover, a significant inhibition of the inflammasome activation was observed in neopterin pre-conditioned human astrocytes, when challenged with LPS, by reducing IL-1β, caspase-1 and ASC expression or content, components of the NLRP3 inflammasome. Mechanistically, neopterin might induce eletrophilic stress and consequently the nuclear translocation of the transcription factor Nrf-2, and the anti-inflammatory cytokines IL-10 and IL-1ra release, which would induce the inhibition of the inflammasome activation. Altogether, this strongly suggests an essential role of neopterin during inflammatory processes.Human neurons and astrocytes secrete neopterin under inflammatory conditions.Neopterin synthesis precedes inflammasome activation in the mouse hippocampus.Neopterin pre-conditioning inhibits inflammasome activation in human astrocytes.Neopterin preconditioning triggers Nrf2 activation.