Estrogen Receptor β Activation Inhibits Colitis by Promoting the NLRP6-Mediated Autophagy
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PROVIDER: PRJNA637511 | ENA |
REPOSITORIES: ENA
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Project description:Estrogen receptor β (ERβ) and NOD-, LRR- and pyrin domain-containing 6 (NLRP6) are highly expressed in intestinal tissues and reduce intestinal inflammation, but their underlying mechanisms are unclear. We found that ERβ and NLRP6 levels were reduced in patients with inflammatory bowel disease (IBD), and that deletion of ERβ or NLRP6 was exacerbated colitis in mouse models. We discovered that ERβ exerted its anti-inflammatory activity by inducing NLRP6-mediated autophagy. Specifically, ERβ directly regulated NLRP6 gene expression and NLRP6 inflammasome activation through genomic and non-genomic effects. NLRP6 directly interacted with multiple autophagy-related proteins (including ULK1, BECN1, ATG5-ATG12-ATG16L1 complex, p62, and PHB2). Autophagy stimulation suppresses the inflammatory response by eliminating excess ERβ, NLRP6, ASC, Casp-1, IL-1β, TNF-α and damaged mitochondria. These findings indicate that ERβ-NLRP6-autophagy forms a negative feedback loop to maintain intestinal epithelial cell homeostasis and facilitate tissue repair.
2023-06-05 | GSE151864 | GEO
Project description:To identify NLRP6-associated proteins in living cells, we applied an APEX2-based labelling method combined with mass spectrometry. In brief, APEX2 was genetically fused to NLRP6. In the presence of hydrogen peroxide, APEX2 catalysed biotin-phenol to become a biotin-phenol radical that covalently bound to NLRP6 neighbouring proteins (<20 nm). The biotinylated proteins were enriched and collected by streptavidin beads. One-dimensional SDS–PAGE followed by liquid chromatography-tandem mass spectrometry (GeLC–MS/MS) was performed to identify the proteins. To detect ubiquitinated p85α, a Flag-tagged p85α plasmid was transfected into cells. The cell lysates were immunoprecipitated with anti-Flag and separated on a 6% SDS–PAGE gel. After in-gel digestion, the resulting peptides were extracted for GeLC–MS/MS analysis.
2023-07-02 | PXD037460 | Pride
Project description:To identify NLRP6-associated proteins in living cells, we applied an APEX2-based labelling method combined with mass spectrometry. In brief, APEX2 was genetically fused to NLRP6. In the presence of hydrogen peroxide, APEX2 catalysed biotin-phenol to become a biotin-phenol radical that covalently bound to NLRP6 neighbouring proteins (<20 nm). The biotinylated proteins were enriched and collected by streptavidin beads. One-dimensional SDS–PAGE followed by liquid chromatography-tandem mass spectrometry (GeLC–MS/MS) was performed to identify the proteins. To detect ubiquitinated p85α, a Flag-tagged p85α plasmid was transfected into cells. The cell lysates were immunoprecipitated with anti-Flag and separated on a 6% SDS–PAGE gel. After in-gel digestion, the resulting peptides were extracted for GeLC–MS/MS analysis.
2023-07-02 | PXD037436 | Pride
Project description:Nlrp6-/- lamina propria Ly6C-hi monocytes in response to AOM/DSS have deficient TNFα production, but increased production of other pro-inflammatory cytokines as compared to WT NLRP6 is a member of the Nod-like receptor family, whose members are involved in the recognition of microbes and/or tissue injury. NLRP6 was previously demonstrated to regulate the production of IL-18 and is important for protecting mice against chemically-induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms by which NLRP6 reduces susceptibility to colonic inflammation remain unclear. Here, we determined that NLRP6 expression is specifically upregulated in Ly6Chi inflammatory monocytes that infiltrate into the colon during dextran sulfate sodium (DSS)-induced inflammation. Adoptive transfer of WT Ly6Chi inflammatory monocytes into Nlrp6-/- mice was sufficient to protect them from mortality, significantly reducing intestinal permeability and damage. NLRP6-deficient inflammatory monocytes were specifically defective in TNFα production, which was important for reducing DSS-induced mortality and dependent on autocrine IL-18 signaling by inflammatory monocytes. Our data reveal a previously unappreciated role for NLRP6 in inflammatory monocytes, which are recruited during intestinal injury to promote barrier function and limit bacteria-driven inflammation. This study also highlights the importance of early cytokine responses, particularly NLRP6-dependent and IL-18-dependent TNFα production in preventing chronic dysregulated inflammation. Ly6Chi monocytes were sorted from lamina propria of WT or Nlrp6-/- mice at day 10 of AOM/2%DSS. RNA was extracted and hybridized to the mouse 2.1 ST array.
2016-03-27 | E-GEOD-79631 | biostudies-arrayexpress
Project description:Nlrp6 is expressed by T cells, but whether Nlrp6 influences the transcriptom of T cells is not known Methods: Equal numbers of Wild Type and Nlrp6-/- CD4 T cells were adoptively transfered in RAG-/- hosts, isolated from the colonic lamina propria and mRNA profiles gernerated by next generation squencing in quadruplicates using Illumina squencers. Conclusions: Our study indicates that Nlrp6 may regulate genes that are involved in apoptosis of T cells
2019-05-08 | GSE116454 | GEO
Project description:Nlrp6-/- lamina propria Ly6C-hi monocytes in response to AOM/DSS have deficient TNFα production, but increased production of other pro-inflammatory cytokines as compared to WT NLRP6 is a member of the Nod-like receptor family, whose members are involved in the recognition of microbes and/or tissue injury. NLRP6 was previously demonstrated to regulate the production of IL-18 and is important for protecting mice against chemically-induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms by which NLRP6 reduces susceptibility to colonic inflammation remain unclear. Here, we determined that NLRP6 expression is specifically upregulated in Ly6Chi inflammatory monocytes that infiltrate into the colon during dextran sulfate sodium (DSS)-induced inflammation. Adoptive transfer of WT Ly6Chi inflammatory monocytes into Nlrp6-/- mice was sufficient to protect them from mortality, significantly reducing intestinal permeability and damage. NLRP6-deficient inflammatory monocytes were specifically defective in TNFα production, which was important for reducing DSS-induced mortality and dependent on autocrine IL-18 signaling by inflammatory monocytes. Our data reveal a previously unappreciated role for NLRP6 in inflammatory monocytes, which are recruited during intestinal injury to promote barrier function and limit bacteria-driven inflammation. This study also highlights the importance of early cytokine responses, particularly NLRP6-dependent and IL-18-dependent TNFα production in preventing chronic dysregulated inflammation.
2016-03-27 | GSE79631 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is one of the main causes of liver diseases in the world. At present, the pathogenesis of NAFLD is not completely clear, and the regulatory role of inflammatory corpuscles in NAFLD-related metabolic diseases is increasingly prominent. NLRP6 is a member of the NLRs family of pattern recognition receptors and is related to the occurrence and development of NAFLD, but the specific mechanism is still unclear. We report here that NLRP6 is an important regulator of liver lipid metabolism, and its absence will affect the formation and accumulation of lipid droplets in the liver. In the HFD-induced NAFLD model group, NLRP6 deletion increased the mouse lipid content and aggravated hepatocyte steatosis by up-regulating the expressions of ADRP and CIDEC and down-regulating the expression of ApoB100.On the contrary, overexpression of NLRP6 in hepatocytes can significantly reduce intracellular lipid content and lipid droplets, and reduce the expression of ADRP and CIDEC. Indicated that NLRP6 can inhibit the accumulation of lipid droplets in hepatocytes by regulating the expression of ADRP, CIDEC and ApoB100, and thus alleviating the symptoms of NAFLD.
2024-01-31 | GSE239747 | GEO
Project description:BACKGROUND:Excessive estrogen exposure is an important pathogenic factor in uterine endometrial cancer (UEC). Recent studies have reported the metabolic properties can influence the progression of UEC. However, the underlying mechanisms have not been fully elucidated. METHODS:Glutaminase (GLS), MYC and autophagy levels were detected. The biological functions of estrogen-MYC-GLS in UEC cells (UECC) were investigated both in vivo and in vitro. RESULTS:Our study showed that estrogen remarkably increased GLS level through up-regulating c-Myc, and enhanced glutamine (Gln) metabolism in estrogen-sensitive UEC cell (UECC), whereas fulvestrant (an ER inhibitor antagonist) could reverse these effects. Estrogen remarkably promoted cell viability and inhibited autophagy of estrogen sensitive UECC. However, CB-839, a potent selective oral bioavailable inhibitor of both splice variants of GLS, negatively regulated Gln metabolism, and inhibited the effects of Gln and estrogen on UECC's growth and autophagy in vitro and / or in vivo. CONCLUSIONS:CB-839 triggers autophagy and restricts growth of UEC by suppressing ER/Gln metabolism, which provides new insights into the potential value of CB-839 in clinical treatment of estrogen-related UEC.
| S-EPMC6700828 | biostudies-literature
Project description:CD103+ and CD103- B cells from Wildtype Non-obese diabetic mice and NLRP6-deficient (ko) NOD mice were investigated for their gene expression All B cells were isolated from the spleen of female non-diabetic mice aged 12-16 weeks and gated on Live, single TCRbeta-CD11c-CD11b-CD19+
2023-02-08 | GSE224472 | GEO
Project description:Liver cancer exhibits significant gender disparities, with men having a 2-5 times higher risk of developing liver cancer compared to women. Numerous studies have demonstrated the influence of estrogen on liver cancer development, although the precise underlying mechanism remains unclear. Peroxiredoxins (PRDXs) represent a recently identified peroxidase family that modulates various signaling pathways associated with reactive oxygen species. This research aims to explore the impact of estrogen on the expression of PRDX1, PRDX5, and PRDX6 in hepatocellular carcinoma cells, thereby modulating liver cancer progression. Treatment with estrogen and the silencing of PRDX1, PRDX5, and PRDX6 impairs the proliferative capacity of hepatocarcinoma cells. The levels of PRDX1, PRDX5, and PRDX6 were found to be elevated in hepatocellular carcinoma compared to normal tissues, with estrogen demonstrating the ability to decrease their expression in hepatocellular carcinoma cells. Furthermore, estrogen influences the expression of PRDXs (PRDX5 and PRDX6) by regulating RASA1. Additionally, estrogen stimulation impacts ferroptosis in hepatocellular carcinoma cells, suggesting that PRDXs and ferroptosis-related genes are estrogen-responsive genes that promote liver cancer progression. Elevated LPCAT3 levels and downregulation of PRDX1, PRDX5, and PRDX6 expression may potentially manage the advancement of HCC.
2024-08-26 | PXD055317 |