TY - JOUR
T1 - Melatonin administration to wild-type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis
AU - Rahim, Ibtissem
AU - Djerdjouri, Bahia
AU - Sayed, Ramy K.
AU - Fernández-Ortiz, Marisol
AU - Fernández-Gil, Beatriz
AU - Hidalgo-Gutiérrez, Agustín
AU - López, Luis C.
AU - Escames, Germaine
AU - Reiter, Russel J.
AU - Acuña-Castroviejo, Darío
N1 - Funding Information:
This study was partially supported by grants from the Ministerio de Economia, Industria y Competitividad y por el Fondo de Desarrollo Regional FEDER, Spain n? RD12/0043/0005; PI08-1664; PI13-00981; CB16-10-00238), and from the Consejer?a de Innovaci?n, Ciencia y Empresa, Junta de Andaluc?a (P07-CTS-03135, P10-CTS-5784, and CTS-101), Spain. The authors thank to Iryna Rusanova for her technical support. M F-O is supported by a FPU fellowship from the Ministerio de Educaci?n, Cultura y Deporte, Spain, and LCL is supported by the ?Ram?n y Cajal? National Program (Ministerio de Econom?a y Competitividad, Spain).
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
KW - NF-κB
KW - NLRP3 deficiency
KW - NLRP3 inflammasome
KW - heart
KW - melatonin
KW - sepsis
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U2 - 10.1111/jpi.12410
DO - 10.1111/jpi.12410
M3 - Article
C2 - 28370493
AN - SCOPUS:85018363813
VL - 63
JO - Journal of Pineal Research
JF - Journal of Pineal Research
SN - 0742-3098
IS - 1
M1 - e12410
ER -