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Role of neopterin on inflammasome activation in the nervous system
thesisposted on 2022-03-28, 02:10 authored by Roberta De Paula Martins
The inflammasome is a protein complex responsible for the maturation of the pro-inflammatory cytokines, pro-IL-1β and pro-IL-18. It represents a key event in the pathogenesis of inflammatory diseases which can be triggered by reactive oxygen species (ROS). Neopterin, , an endogenous pteridin, is considered an early and sensitive biomarker of immune system activation. Although elevated neopterin levels have been associated with oxidative stress and inflammation for decades, the role of the pteridine in these conditions also remains unclear. Therefore, we investigated neopterin production in the central nervous system (CNS) under inflammatory conditions and the effect of neopterin preconditioning on inflammasome activation in nervous cells. A single lipopolysaccharide (LPS) (0.33 mg/kg; intraperitoneal) injection elicited an early hippocampal and serum increase of neopterin levels in adult Swiss mice, which occurred in parallel with inflammasome activation. It was also observed that rat cortical astrocytes produced and released neopterin under mitochondrial stress. In addition, extracellular neopterin (50 nM) inhibited ROS production and increased heme-oxygenase-1 (HO-1) content, an inducible antioxidant enzyme controlled by Nrf2 (nuclear factor (erythroid-derived 2)-like 2), which was also increased by the pteridine. Aiming to better understand the role of neopterin, we evaluated the effect of neopterin preconditioning on LPS-induced inflammasome activation in human primary nerve cells. Neopterin inhibited the inflammasome activation in astrocytes and neurons. Moreover, neopterin increased the anti-inflammatory cytokines IL-10 and IL-1Ra astrocytic release. Finally, we analysed the levels of neopterin and cytokines in the serum of patients diagnosed with Autism Spectrum Disorders (ASD), a disease whose the pathophysiology remains virtually unknown. Higher neopterin and IL-10 and IL-1Ra levels were observed in ASD patients, while IL-1β, TNF-α and IL-6 did not change. In conclusion, neopterin appears to induce neuroprotective functions, when produced before or in parallel with the inflammatory stimulus in the CNS, by favoring oxidative stress resistance and inhibiting inflammasome assembly. The proposed molecular mechanism for this effect is through the activation of the Nrf2/HO-1 cytoprotective pathway.