Nuclear Receptor Subfamily 1 Group D Member 1 Regulates Circadian Activity of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice

Pourcet, Benoît; Zecchin, Mathilde; Ferri, Lise; Beauchamp, Justine; Sitaula, Sadicha; Billon, Cyrielle; Delhaye, Stéphane; Vanhoutte, Jonathan; Mayeuf-Louchart, Alicia; Thorel, Quentin; Haas, Joel T.; Eeckhoute, Jérôme; Dombrowicz, David; Duhem, Christian; Boulinguiez, Alexis; Lancel, Steve; Sebti, Yasmine; Burris, Thomas P.; Staels, Bart; Duez, Hélène

doi:10.1053/j.gastro.2017.12.019

Cited by 170 publications

(193 citation statements)

References 59 publications

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“…We recently demonstrated that the nuclear receptor REV-ERB␣ plays a role in regulation of the NLRP3 inflammasome (15). Bone marrow-derived macrophages (BMDMs) from Rev-erb␣-null mice display elevated Nlpr3 and Il1b gene expression due to the inability of REV-ERB to suppress the expression of these genes (15). Given that ROR␥ often functions in a reciprocal manner to REV-ERB, we performed a similar experiment in BMDMs from ROR␥-null mice.…”

Section: Ror␥ Is Required For Normal Nlrp3 Inflammasome Activity In Mmentioning

confidence: 99%

“…Based on our data indicating that ROR␥ is required for normal expression of Nlrp3 and Il1b as well as our recent study describing the direct regulation of these genes by REV-ERB, a nuclear receptor that typically recognizes similar or identical response elements as ROR (18), we sought to determine whether ROR␥ directly binds to response elements in the pro-ACCELERATED COMMUNICATION: ROR␥ regulates the NLRP3 inflammasome moters of the Nlrp3 and Il1b genes. Two functional REV-ERB response elements were identified in the promoter of the Il1b gene and four were identified in the promoter of the Nlrp3 gene (15), and we focused on determining whether these were also bound by ROR␥ using ChIP (Fig. 3A).…”

Section: Ror␥ Response Elements Are Located In the Promoters Of The Nmentioning

confidence: 99%

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RORγ regulates the NLRP3 inflammasome

Billon

Murray

Avdagic

et al. 2019

Journal of Biological Chemistry

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Edited by Luke O'NeillRAR-related orphan receptor ␥ (ROR␥) 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)-1␤ into a mature cytokine. Elevated activity of the NLRP3 inflammasome contributes to the progression of an array of inflammatory diseases. Bone marrowderived macrophages (BMDMs) isolated from ROR␥-null mice displayed reduced capacity to secrete IL-1␤, 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 ROR␥. ROR␥ inverse agonists were effective inhibitors of the inflammasome. ROR␥ inverse agonists suppressed lipopolysaccharide (LPS)/ATP-stimulated IL-1␤ secretion and expression of Il1b and Nlrp3 in BMDMs. Additionally, the ability of the ROR␥ inverse agonists to suppress IL-1␤ secretion was lost in Nlrp3-null macrophages. The potential for targeting the NLRP3 inflammasome in vivo using ROR␥ inverse agonists was examined in two models: LPS-induced sepsis and fulminant hepatitis. Pharmacological inhibition of ROR␥ activity reduced plasma IL-1␤ as well as IL-1␤ production by peritoneal macrophages in a model of LPS-induced sepsis. Additionally, ROR␥ inverse agonists reduced mortality in an LPS/D-galactosamineinduced fulminant hepatitis mouse model. These results illustrate a major role for ROR␥ in regulation of innate immunity via modulation of NLRP3 inflammasome activity. Furthermore, these data suggest that inhibiting the NLRP3 inflammasome with ROR␥ inverse agonists may be an effective method to treat NLRP3-associated diseases.

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Section: Ror␥ Is Required For Normal Nlrp3 Inflammasome Activity In Mmentioning

confidence: 99%

Section: Ror␥ Response Elements Are Located In the Promoters Of The Nmentioning

confidence: 99%

RORγ regulates the NLRP3 inflammasome

Billon

Murray

Avdagic

et al. 2019

Journal of Biological Chemistry

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“…NR1D1 is linked to the immune system, as it has been shown to repress Tolllike receptor 4, Cx3cr1, and IL-6 expression in macrophages 15 . Therefore, activated NR1D1 alleviates the progression of pneumonia and fulminant hepatitis 19,20 . NR1D1 regulates the inflammatory response; however, whether NR1D1 mediates the pathogenesis of RA and related mechanisms remain poorly defined.…”

Section: Introductionmentioning

confidence: 99%

NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis

et al. 2020

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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, pannus formation, and cartilage and bone destruction. Nuclear receptor subfamily 1 group D member 1 (NR1D1) functions as a transcriptional repressor and plays a vital role in inflammatory reactions. However, whether NR1D1 is involved in synovial inflammation and joint destruction during the pathogenesis of RA is unknown. In this study, we found that NR1D1 expression was increased in synovial tissues from patients with RA and decreased in RA Fibroblast-like synoviocytes (FLSs) stimulated with IL-1β in vitro. We showed that NR1D1 activation decreased the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs), while NR1D1 silencing exerted the opposite effect. Furthermore, NR1D1 activation reduced reactive oxygen species (ROS) generation and increased the production of nuclear transcription factor E2-related factor 2 (Nrf2)-associated enzymes. Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways were blocked by the NR1D1 agonist SR9009 but activated by NR1D1 silencing. NR1D1 activation also inhibited M1 macrophage polarization and suppressed osteoclastogenesis and osteoclastrelated genes expression. Treatment with NR1D1 agonist SR9009 in collagen-induced arthritis (CIA) mouse significantly suppressed the hyperplasia of synovial, infiltration of inflammatory cell and destruction of cartilage and bone. Our findings demonstrate an important role for NR1D1 in RA and suggest its therapeutic potential.

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“…Based on the observation that hypoxia triggers release of ATP into the extracellular space [24,25], we became interested in whether the ATP level in murine PB changes in a circadian rhythm-dependent manner. We employed the term "zeitgeber; ZT" (translated from the German as "time giver" or "synchronizer"), which was introduced by Jürgen Aschoff, one of the founders of the field of chronobiology, to annotate time points of measurement: ZT1 for 7:00 am, ZT5 for 11:00 am; ZT13 for 7:00 pm, and ZT21 for 3:00 am.…”

Section: Diurnal Changes In the Pb Level Of Extracellular Atp Occur Imentioning

confidence: 99%

“…Diurnal Changes in Expression of the Circadian Clock Gene NR1D1 As Well as the Aim2, Nlrp1a, and Nlrp1b Inflammasomes Nuclear receptor subfamily group D member 1 (NR1D1) protein has recently been described as reducing the circadian activity of the Nlrp3 inflammasome during fulminant hepatitis in mice [25]. Therefore, we selected this circadian clock gene and evaluated the circadian changes in expression of NR1D1 mRNA in peripheral blood granulocytes.…”

Section: Diurnal Changes In the Expression Of Genes From The Nlrp3 Inmentioning

confidence: 99%

Novel Evidence that Purinergic Signaling - Nlrp3 Inflammasome Axis Regulates Circadian Rhythm of Hematopoietic Stem/Progenitor Cells Circulation in Peripheral Blood

Adamiak

Ciechanowicz

Skoda

et al. 2020

Stem Cell Rev and Rep

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We found that circadian changes in ATP level in peripheral blood (PB) activate the Nlrp3 inflammasome, which triggers diurnal release of hematopoietic stem/progenitor cells (HSPCs) from murine bone marrow (BM) into PB. Consistent with this finding, we observed circadian changes in expression of mRNA for Nlrp3 inflammasome-related genes, including Nlrp3, caspase 1, IL-1β, IL-18, gasdermin (GSDMD), HMGB1, and S100A9. Circadian release of HSPCs from BM into PB as well as expression of Nlrp3-associated genes was decreased in mice in which pannexin 1-mediated secretion of ATP was inhibited by the blocking peptide 10Panx and in animals exposed to the specific small-molecule inhibitor of the Nlrp3 inflammasome MCC950. In addition to HSPCs, a similar decrease in diurnal cell counts was observed for mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like stem cells (VSELs). These results shed more light on the complexity of circadian regulation of HSPC release into PB, which is coordinated in a purinergic signaling-, innate immunity-dependent manner. Moreover, in addition to circadian changes in expression of the Nlrp3 inflammasome we also observed diurnal changes in expression of other inflammasomes, including Aim2, Nrp1a, and Nlrp1b.

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Nuclear Receptor Subfamily 1 Group D Member 1 Regulates Circadian Activity of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice

Cited by 170 publications

References 59 publications

RORγ regulates the NLRP3 inflammasome

RORγ regulates the NLRP3 inflammasome

NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis

Novel Evidence that Purinergic Signaling - Nlrp3 Inflammasome Axis Regulates Circadian Rhythm of Hematopoietic Stem/Progenitor Cells Circulation in Peripheral Blood

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