BIOMAT Database Logo BIOMAT Database Logo

Pregnane X Receptor Activation Triggers Rapid ATP Release in Primed Macrophages That Mediates NLRP3 Inflammasome Activation. 2019

Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
Departments of Physiology and Pharmacology (G.H., K.L.F., V.K.P.V., L.A., S.A.H.), Biochemistry and Molecular Biology (C.F.S., J.A.M.), Medicine (D.A.M.), and Immunology, Microbiology, and Infectious Diseases (S.A.H.), University of Calgary, Calgary, Alberta, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (T.K.H.C.); and Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (S.M.).

The pregnane X receptor (PXR) is a ligand-activated nuclear receptor that acts as a xenobiotic sensor, responding to compounds of foreign origin, including pharmaceutical compounds, environmental contaminants, and natural products, to induce transcriptional events that regulate drug detoxification and efflux pathways. As such, the PXR is thought to play a key role in protecting the host from xenobiotic exposure. More recently, the PXR has been reported to regulate the expression of innate immune receptors in the intestine and modulate inflammasome activation in the vasculature. In the current study, we report that activation of the PXR in primed macrophages triggers caspase-1 activation and interleukin-1β release. Mechanistically, we show that this response is nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3-dependent and is driven by the rapid efflux of ATP and P2X purinoceptor 7 activation following PXR stimulation, an event that involves pannexin-1 gating, and is sensitive to inhibition of Src-family kinases. Our findings identify a mechanism whereby the PXR drives innate immune signaling, providing a potential link between xenobiotic exposure and the induction of innate inflammatory responses.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008264 Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood MONOCYTES. Main types are PERITONEAL MACROPHAGES; ALVEOLAR MACROPHAGES; HISTIOCYTES; KUPFFER CELLS of the liver; and OSTEOCLASTS. They may further differentiate within chronic inflammatory lesions to EPITHELIOID CELLS or may fuse to form FOREIGN BODY GIANT CELLS or LANGHANS GIANT CELLS. (from The Dictionary of Cell Biology, Lackie and Dow, 3rd ed.) Bone Marrow-Derived Macrophages,Monocyte-Derived Macrophages,Macrophage,Macrophages, Monocyte-Derived,Bone Marrow Derived Macrophages,Bone Marrow-Derived Macrophage,Macrophage, Bone Marrow-Derived,Macrophage, Monocyte-Derived,Macrophages, Bone Marrow-Derived,Macrophages, Monocyte Derived,Monocyte Derived Macrophages,Monocyte-Derived Macrophage
D009419 Nerve Tissue Proteins Proteins, Nerve Tissue,Tissue Proteins, Nerve
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000071199 NLR Family, Pyrin Domain-Containing 3 Protein An NLR protein that contains an N-terminal PYRIN DOMAIN and ATP-binding site and 9 C-terminal LEUCINE-rich repeats; it is expressed primarily by MACROPHAGES. It is a core component of the INFLAMMASOME and directs its assembly in response to pathogen infection and damage-associated stimuli. Mutations in the NLRP3 gene are associated with FAMILIAL COLD AUTOINFLAMMATORY SYNDROME. Cold Autoinflammatory Syndrome 1 Protein,NACHT, LRR and PYD Domains-Containing Protein 3,NLRP3 Protein,NACHT, LRR and PYD Domains Containing Protein 3,NLR Family, Pyrin Domain Containing 3 Protein
D000077297 Pregnane X Receptor Steroid receptor that binds and is activated by variety of endogenous compounds and XENOBIOTICS. It binds the response element in promoters of genes that encode CYTOCHROME P450 3A4 and ATP BINDING CASSETTE TRANSPORTER, SUBFAMILY B, MEMBER 1 proteins, and also activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs, and endogenous compounds. It is activated by the antibiotic RIFAMPICIN and various plant metabolites, such as hyperforin, guggulipid, colupulone, and ISOFLAVONES. NR1I2,Nuclear Receptor Subfamily 1, Group I, Member 2,SXR Receptor,Steroid X Receptor,Steroid and Xenobiotic Receptor
D000255 Adenosine Triphosphate An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
Paxillin mediates ATP-induced activation of P2X7 receptor and NLRP3 inflammasome.
November 2020, BMC biology,
Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
ATP release and purinergic signaling in NLRP3 inflammasome activation.
January 2012, Frontiers in immunology,
Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
Calcium sensing receptor activation in THP-1 macrophages triggers NLRP3 inflammasome and human preadipose cell inflammation.
February 2020, Molecular and cellular endocrinology,
Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
Xenobiotic pregnane X receptor (PXR) regulates innate immunity via activation of NLRP3 inflammasome in vascular endothelial cells.
October 2014, The Journal of biological chemistry,
Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes.
January 2020, Cell & bioscience,
Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages.
February 2017, Cell death & disease,
Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages.
February 2023, Cellular & molecular immunology,
Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
S1P/S1P2 Signaling Axis Regulates Both NLRP3 Upregulation and NLRP3 Inflammasome Activation in Macrophages Primed with Lipopolysaccharide.
October 2021, Antioxidants (Basel, Switzerland),
Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
Intracellular ATP Decrease Mediates NLRP3 Inflammasome Activation upon Nigericin and Crystal Stimulation.
December 2015, Journal of immunology (Baltimore, Md. : 1950),
Grace Hudson, and Kyle L Flannigan, and Vivek Krishna Pulakazhi Venu, and Laurie Alston, and Christina F Sandall, and Justin A MacDonald, and Daniel A Muruve, and Thomas K H Chang, and Sridhar Mani, and Simon A Hirota
Vibrio alginolyticus Triggers Inflammatory Response in Mouse Peritoneal Macrophages via Activation of NLRP3 Inflammasome.
January 2021, Frontiers in cellular and infection microbiology,
Copied contents to your clipboard!