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-
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