PMID- 30455347
OWN - NLM
STAT- MEDLINE
DCOM- 20190409
LR  - 20210314
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 294
IP  - 1
DP  - 2019 Jan 4
TI  - RORgamma regulates the NLRP3 inflammasome.
PG  - 10-19
LID - S0021-9258(20)36869-1 [pii]
LID - 10.1074/jbc.AC118.002127 [doi]
AB  - RAR-related orphan receptor gamma (RORgamma) is a nuclear receptor that plays an 
      essential role in the development of T helper 17 (T(h)17) cells of the adaptive 
      immune system. The NLRP3 inflammasome is a component of the innate immune system 
      that processes interleukin (IL)-1beta into a mature cytokine. Elevated activity of 
      the NLRP3 inflammasome contributes to the progression of an array of inflammatory 
      diseases. Bone marrow-derived macrophages (BMDMs) isolated from RORgamma-null mice 
      displayed reduced capacity to secrete IL-1beta, and they also displayed a reduction 
      in Nlrp3 and Il1b gene expression. Examination of the promoters of the Il1b and 
      Nlrp3 genes revealed multiple putative ROR response elements (ROREs) that were 
      occupied by RORgamma. RORgamma inverse agonists were effective inhibitors of the 
      inflammasome. RORgamma inverse agonists suppressed lipopolysaccharide 
      (LPS)/ATP-stimulated IL-1beta secretion and expression of Il1b and Nlrp3 in BMDMs. 
      Additionally, the ability of the RORgamma inverse agonists to suppress IL-1beta 
      secretion was lost in Nlrp3-null macrophages. The potential for targeting the 
      NLRP3 inflammasome in vivo using RORgamma inverse agonists was examined in two 
      models: LPS-induced sepsis and fulminant hepatitis. Pharmacological inhibition of 
      RORgamma activity reduced plasma IL-1beta as well as IL-1beta production by peritoneal 
      macrophages in a model of LPS-induced sepsis. Additionally, RORgamma inverse agonists 
      reduced mortality in an LPS/d-galactosamine-induced fulminant hepatitis mouse 
      model. These results illustrate a major role for RORgamma in regulation of innate 
      immunity via modulation of NLRP3 inflammasome activity. Furthermore, these data 
      suggest that inhibiting the NLRP3 inflammasome with RORgamma inverse agonists may be 
      an effective method to treat NLRP3-associated diseases.
CI  - (c) 2019 Billon et al.
FAU - Billon, Cyrielle
AU  - Billon C
AD  - Center for Clinical Pharmacology, Washington University School of Medicine and 
      St. Louis College of Pharmacy, St. Louis, Missouri 63110.
FAU - Murray, Meghan H
AU  - Murray MH
AD  - Department of Pharmacology and Physiology, Saint Louis University School of 
      Medicine, St. Louis, Missouri 63104.
FAU - Avdagic, Amer
AU  - Avdagic A
AD  - Center for Clinical Pharmacology, Washington University School of Medicine and 
      St. Louis College of Pharmacy, St. Louis, Missouri 63110.
FAU - Burris, Thomas P
AU  - Burris TP
AD  - Center for Clinical Pharmacology, Washington University School of Medicine and 
      St. Louis College of Pharmacy, St. Louis, Missouri 63110. Electronic address: 
      burristhomas@wustl.edu.
LA  - eng
GR  - R01 MH092769/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20181119
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (IL1B protein, mouse)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Nuclear Receptor Subfamily 1, Group F, Member 3)
RN  - 0 (Rorc protein, mouse)
RN  - 7535-00-4 (Galactosamine)
SB  - IM
MH  - Animals
MH  - Galactosamine/toxicity
MH  - *Immunity, Innate
MH  - Inflammasomes/genetics/*immunology
MH  - Interleukin-1beta/genetics/immunology
MH  - Lipopolysaccharides/toxicity
MH  - Liver Failure, Acute/chemically induced/genetics/immunology/pathology
MH  - Macrophages/*immunology/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/*immunology
MH  - Nuclear Receptor Subfamily 1, Group F, Member 3/genetics/*immunology
MH  - Response Elements/immunology
MH  - Sepsis/chemically induced/genetics/immunology/pathology
MH  - Th17 Cells/*immunology/pathology
PMC - PMC6322869
OTO - NOTNLM
OT  - drug discovery
OT  - inflammasome
OT  - innate immunity
OT  - interleukin 1 (IL-1)
OT  - liver
OT  - liver injury
OT  - macrophage
OT  - nuclear receptor
OT  - transcription factor
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2018/11/21 06:00
MHDA- 2019/04/10 06:00
PMCR- 2020/01/04
CRDT- 2018/11/21 06:00
PHST- 2018/01/29 00:00 [received]
PHST- 2018/11/05 00:00 [revised]
PHST- 2018/11/21 06:00 [pubmed]
PHST- 2019/04/10 06:00 [medline]
PHST- 2018/11/21 06:00 [entrez]
PHST- 2020/01/04 00:00 [pmc-release]
AID - S0021-9258(20)36869-1 [pii]
AID - AC118.002127 [pii]
AID - 10.1074/jbc.AC118.002127 [doi]
PST - ppublish
SO  - J Biol Chem. 2019 Jan 4;294(1):10-19. doi: 10.1074/jbc.AC118.002127. Epub 2018 
      Nov 19.