Melatonin Reduces NLRP3 Inflammasome Activation by Increasing α7 nAChR-Mediated Autophagic Flux

Abstract

Microglia controls the immune system response in the brain. Specifically, the activation and dysregulation of the NLRP3 inflammasome is responsible for the initiation of the inflammatory process through IL-1β and IL-18 release. In this work, we have focused on studying the effect of melatonin on the regulation of the NLRP3 inflammasome through α7 nicotinic receptor (nAChR) and its relationship with autophagy. For this purpose, we have used pharmacological and genetic approaches in lipopolysaccharide (LPS)-induced inflammation models in both in vitro and in vivo models. In the BV2 cell line, LPS inhibited autophagy, which increased NLRP3 protein levels. However, melatonin promoted an increase in the autophagic flux. Treatment of glial cultures from wild-type (WT) mice with LPS followed by extracellular adenosine triphosphate (ATP) produced the release of IL-1β, which was reversed by melatonin pretreatment. In cultures from α7 nAChR knock-out (KO) mice, melatonin did not reduce IL-1β release. Furthermore, melatonin decreased the expression of inflammasome components and reactive oxygen species (ROS) induced by LPS; co-incubation of melatonin with α-bungarotoxin (α-bgt) or luzindole abolished the anti-inflammatory and antioxidant effects. In vivo, melatonin reverted LPS-induced cognitive decline, reduced NLRP3 levels and promoted autophagic flux in the hippocampi of WT mice, whereas in α7 nAChR KO mice melatonin effect was not observed. These results suggest that melatonin may modulate the complex interplay between α7 nAChR and autophagy signaling.

Melatonin and Microglia

“…Suppression of the formation and activity of the NLRP3 inflammasome caused by melatonin was observed after LPS treatment in natural microglia in vivo [ 32 ] and in BV2 cells [ 33 ] as well as in an inflammation model of intracerebral hemorrhage in which BV2 cells were treated with thrombin [ 34 ]. In the latter study, conditioned medium from thrombin-treated BV2 cells was also shown to induce apoptosis in HT22 cells, an effect suppressed by the addition of melatonin.…”

Pharmacological Blocker of NF-κb and Mitochondrial Ros Restrict NLRP3 Inflammasome Activation and Rescue Dopaminergic Neurons in Vitro and in Vivo Parkinson’s Disease

“…Remarkably, H 2 O 2 -treatment at a dose of 100 µM causes a robust increase in NLRP3 activation along with cleavage of caspase-1 and release of mature IL-1β level and IL-18 level in LPS primed microglia which remains as potent pro-in ammatory cytokines for further exacerbating neuroin ammatory cascade following neurodegeneration. Similar studies in microglia and macrophages have shown the NLRP3 in ammasome activation with LPS priming following extracellular ATP treatment but not with LPS or ATP alone [55,56]. Contrary to this a few studies states the in ammasome activation occurs only by LPS priming but not its downstream cascade proteins (IL-1β, IL-18) [57,58].…”

The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy

“…However, the initiation of melatonin supplementation must be carefully addressed to ensure its antiinflammatory potential [31]. However it is hypothesized that the anti-inflammatory activity of melatonin is mainly achieved by orchestrating the suppression of toll-like receptor (TLR) signaling [175], the inhibition of the multiprotein platform inflammasome promoter NLRP3 (Nucleotide-binding Oligomerization Domain (NOD)-Like Receptor Pyrin domain containing 3) [176], and the blockage of the nuclear translocation of the NF-κB [76]. The result of binding viral proteins and/or genomic ssRNA by TLR/PAMPs would be the recruitment of the receptor-ligand complexes and the activation of apoptosis, lysosomal autophagy, and inflammasome-induced pyroptosis for the clearance of the virus [166].…”