Melatonin administration to wild‐type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis

Abstract

The NLRP3 inflammasome is involved in the innate immune response during inflammation. Moreover, melatonin blunts the NF-κB/NLRP3 connection during sepsis. Thus, we compared the roles of the NLRP3 inflammasome and/or melatonin treatment in the septic response of wild-type and NLRP3 mice. Mouse myocardial tissue was used for this purpose. The nuclear turnover of NF-κB was enhanced during sepsis, with an increase in TNFα, iNOS, and pro-IL-1β. The lack of inflammasome in NLRP3 mice significantly reduced that response and blunted IL-1β maturation due to the lack of caspase-1. Clock and Bmal1 did not change in both mouse strains, enhancing Chrono expression in mutants. RORα, which positively regulates Bmal1, was enhanced at a similar extend in both mouse strains, whereas the expression of the Bmal1 repressor, Rev-Erbα, increased in WT but was depressed in NLRP3 mice. Nampt, transcriptionally controlled by Bmal1, increased in WT mice together with Sirt1, whereas they remained unchanged in NLRP3 mice. Melatonin treatment reduced the septic response in a comparable manner as did the lack of NLRP3, but unlike the latter, it normalized the clock genes turnover through the induction of RORα and repression of Rev-Erbα and Per2, leading to enhanced Nampt and Sirt1. The lack of NLRP3 inflammasome converts sepsis to a moderate inflammatory disease and identifies NLRP3 as a main target for the treatment of sepsis. The efficacy of melatonin in counteracting the NLRP3 inflammasome activation further confirms the indoleamine as a useful therapeutic drug against this serious condition.

Melatonin prevents early pituitary dysfunction induced by sucrose‐rich diets

“…Melatonin treatment not only prevented the increase in the number of macrophages but also blocked the induction of IL‐1β and components of the NLP3‐inflammasome in the adenohypophysis. In agreement with our results, prevention of NLP3‐inflammasome activation by melatonin has been demonstrated in inflammatory diseases and sepsis . In harmony with these results, melatonin has been shown to favor the anti‐inflammatory M2 phenotype over M1 in liver Kupffer cells, peritoneal macrophages, and splenocytes from stressed mice …”

Melatonin alleviates inflammasome‐induced pyroptosis through inhibiting NF‐κB/GSDMD signal in mice adipose tissue

“…Studies have identified that NF‐κB could bind to TLR4 and NLRP3 promoter region, suggesting the transcriptional regulation of NF‐κB on TLR4 and NLRP3 and its downstream targets . Furthermore, melatonin could suppress NF‐κB‐dependent pro‐inflammatory mediators in various cell types . From these findings, we surmise that melatonin may participate in the regulation of NLRP3 inflammasome by modulating the NF‐κB signal in adipocytes.…”

Melatonin Supplementation, a Strategy to Prevent Neurological Diseases through Maintaining Integrity of Blood Brain Barrier in Old People

“…Melatonin has shown protective effect on BBB integrity via a variety of pathways: inhibition of the toll like receptor 4 (TLR4)/NF-κB signaling pathway in neonatal rats (Hu et al, 2017), inhibition of NADPH oxidase-2 (Jumnongprakhon et al, 2016), inhibition of MMP-9 (Alluri et al, 2016), inhibiton of AMP-activated protein kinase (AMPK) activation (Wang et al, 2017) and impact on silent information regulator 1 (SIRT1; Zhao et al, 2015) and NLRP3 inflammasome (Rahim et al, 2017). …”

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