Melatonin administration to wild‐type mice and nontreated NLRP 3 mutant mice share similar inhibition of the inflammatory response during sepsis
Abstract The NLRP 3 inflammasome is involved in the innate immune response during inflammation. Moreover, melatonin blunts the NF ‐κB/ NLRP 3 connection during sepsis. Thus, we compared the roles of the NLRP 3 inflammasome and/or melatonin treatment in the septic response of wild‐type and NLRP 3 −/−...
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Published in | Journal of pineal research Vol. 63; no. 1 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
01.08.2017
|
Online Access | Get full text |
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Summary: | Abstract
The
NLRP
3 inflammasome is involved in the innate immune response during inflammation. Moreover, melatonin blunts the
NF
‐κB/
NLRP
3 connection during sepsis. Thus, we compared the roles of the
NLRP
3 inflammasome and/or melatonin treatment in the septic response of wild‐type and
NLRP
3
−/−
mice. Mouse myocardial tissue was used for this purpose. The nuclear turnover of
NF
‐κB was enhanced during sepsis, with an increase in
TNF
α,
iNOS
, and pro‐
IL
‐1β. The lack of inflammasome in
NLRP
3
−/−
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.
ROR
α, 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
NLRP
3
−/−
mice. Nampt, transcriptionally controlled by Bmal1, increased in
WT
mice together with Sirt1, whereas they remained unchanged in
NLRP
3
−/−
mice. Melatonin treatment reduced the septic response in a comparable manner as did the lack of
NLRP
3, but unlike the latter, it normalized the clock genes turnover through the induction of
ROR
α and repression of Rev–Erbα and Per2, leading to enhanced Nampt and Sirt1. The lack of
NLRP
3 inflammasome converts sepsis to a moderate inflammatory disease and identifies
NLRP
3 as a main target for the treatment of sepsis. The efficacy of melatonin in counteracting the
NLRP
3 inflammasome activation further confirms the indoleamine as a useful therapeutic drug against this serious condition. |
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ISSN: | 0742-3098 1600-079X |
DOI: | 10.1111/jpi.12410 |