NLRP3 inflammasome-mediated neutrophil recruitment and hypernociception depend on leukotriene B(4) in a murine model of gout.

Published on Feb 1, 2012in Arthritis & Rheumatism9.586
· DOI :10.1002/ART.33355
Flávio A. Amaral29
Estimated H-index: 29
(UFMG: Universidade Federal de Minas Gerais),
Vivian V. Costa25
Estimated H-index: 25
(UFMG: Universidade Federal de Minas Gerais)
+ 14 AuthorsMauro M. Teixeira99
Estimated H-index: 99
(UFMG: Universidade Federal de Minas Gerais)
Objective Deposition of monosodium urate monohydrate (MSU) crystals in the joints promotes an intense inflammatory response and joint dysfunction. This study evaluated the role of the NLRP3 inflammasome and 5-lipoxygenase (5-LOX)–derived leukotriene B4 (LTB4) in driving tissue inflammation and hypernociception in a murine model of gout. Methods Gout was induced by injecting MSU crystals into the joints of mice. Wild-type mice and mice deficient in NLRP3, ASC, caspase 1, interleukin-1β (IL-1β), IL-1 receptor type I (IL-1RI), IL-18R, myeloid differentiation factor 88 (MyD88), or 5-LOX were used. Evaluations were performed to assess neutrophil influx, LTB4 activity, cytokine (IL-1β, CXCL1) production (by enzyme-linked immunosorbent assay), synovial microvasculature cell adhesion (by intravital microscopy), and hypernociception. Cleaved caspase 1 and production of reactive oxygen species (ROS) were analyzed in macrophages by Western blotting and fluorometric assay, respectively. Results Injection of MSU crystals into the knee joints of mice induced neutrophil influx and neutrophil-dependent hypernociception. MSU crystal–induced neutrophil influx was CXCR2-dependent and relied on the induction of CXCL1 in an NLRP3/ASC/caspase 1/IL-1β/MyD88–dependent manner. LTB4 was produced rapidly after injection of MSU crystals, and this was necessary for caspase 1–dependent IL-1β production and consequent release of CXCR2-acting chemokines in vivo. In vitro, macrophages produced LTB4 after MSU crystal injection, and LTB4 was relevant in the MSU crystal–induced maturation of IL-1β. Mechanistically, LTB4 drove MSU crystal–induced production of ROS and ROS-dependent activation of the NLRP3 inflammasome. Conclusion These results reveal the role of the NLRP3 inflammasome in mediating MSU crystal–induced inflammation and dysfunction of the joints, and highlight a previously unrecognized role of LTB4 in driving NLRP3 inflammasome activation in response to MSU crystals, both in vitro and in vivo.
📖 Papers frequently viewed together
5 Authors (Fabio Martinon, ..., Jürg Tschopp)
3 Authors (Fabio Martinon, ..., Jürg Tschopp)
#1William John Martin (Malaghan Institute of Medical Research)H-Index: 8
#2Odette M. Shaw (Malaghan Institute of Medical Research)H-Index: 12
Last. Jacquie L. Harper (Malaghan Institute of Medical Research)H-Index: 27
view all 5 authors...
Objective To profile monosodium urate monohydrate (MSU) crystal–recruited monocyte inflammatory function during the course of in vivo differentiation, in a murine model of peritoneal MSU crystal–induced inflammation. Methods C57BL/6J mice were injected intraperitoneally with MSU crystals, and the peritoneal cells were harvested at different time points. The MSU crystal–recruited monocyte/macrophage population was analyzed for the expression of differentiation and activation markers, cytokine pro...
#1Etsushi Kuroda (University of Occupational and Environmental Health Japan)H-Index: 35
#2Ken Ishii (Osaka University)H-Index: 94
Last. Yasuo Morimoto (University of Occupational and Environmental Health Japan)H-Index: 31
view all 9 authors...
Summary Particulates such as silica crystal (silica) and aluminum salts (alum) activate the inflammasome and induce the secretion of proinflammatory cytokines in macrophages. These particulates also induce the production of immunoglobulin E via a T helper 2 (Th2) cell-associated mechanism. However, the mechanism involved in the induction of type 2 immunity has not been elucidated. Here, we showed that silica and alum induced lipopolysaccharide-primed macrophages to produce the lipid mediator pro...
#1Daniela Sachs (UFMG: Universidade Federal de Minas Gerais)H-Index: 21
#2Fernanda M. Coelho (UFMG: Universidade Federal de Minas Gerais)H-Index: 20
Last. Mauro M. Teixeira (UFMG: Universidade Federal de Minas Gerais)H-Index: 99
view all 10 authors...
BACKGROUND AND PURPOSE Chronic joint inflammation and pain are the hallmarks of disease in patients with inflammatory arthritis, notably rheumatoid arthritis. The aim of the present study was to investigate the relative contribution of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and neutrophil influx for joint inflammation and nociception in a novel murine model of antigen-induced arthritis (AIA). EXPERIMENTAL APPROACH AIA was induced by administration of antigen into knee joint of previ...
#1Leo A. B. Joosten (Radboud University Nijmegen Medical Centre)H-Index: 131
#2Mihai G. Netea (Radboud University Nijmegen Medical Centre)H-Index: 162
Last. Jos W. M. van der Meer (Radboud University Nijmegen Medical Centre)H-Index: 115
view all 12 authors...
Objective. The concept that intraarticular crystals of uric acid by themselves trigger episodes of painful gouty arthritis is inconsistent with the clinical reality. Patients with large deposits of monosodium urate monohydrate (MSU) crystals (tophi) do not necessarily experience gouty attacks. In fact, it is the excessive consumption of food or alcohol that elicits the inflammation of the acute gout attack. The aim of this study was to identify the precise mechanism that initiates flares of gout...
#1Richard C. Chou (Harvard University)H-Index: 9
#2Nancy D. Kim (Harvard University)H-Index: 13
Last. Andrew D. Luster (Harvard University)H-Index: 138
view all 9 authors...
Summary A large and diverse array of chemoattractants control leukocyte trafficking, but how these apparently redundant signals collaborate in vivo is still largely unknown. We previously demonstrated an absolute requirement for the lipid chemoattractant leukotriene B 4 (LTB 4 ) and its receptor BLT1 for neutrophil recruitment into the joint in autoantibody-induced arthritis. We now demonstrate that BLT1 is required for neutrophils to deliver IL-1 into the joint to initiate arthritis. IL-1-expre...
#1Hal M. Hoffman (UCSD: University of California, San Diego)H-Index: 67
#2Peter A. ScottH-Index: 8
Last. Ru Liu-Bryan (Veterans Health Administration)H-Index: 8
view all 9 authors...
Objective The mechanism by which monosodium urate monohydrate (MSU) crystals intracellularly activate the cryopyrin inflammasome is unknown. The aim of this study was to use a mouse molecular genetics–based approach to test whether the leucine-rich repeat (LRR) domain of cryopyrin is required for MSU crystal–induced inflammation. Methods Cryopyrin-knockout lacZ (Cryo−Z/−Z) mice and mice with the cryopyrin LRR domain deleted and fused to the lacZ reporter (CryoΔLRR Z/ΔLRR Z) were generated using ...
#1Rongbin Zhou (UNIL: University of Lausanne)H-Index: 31
#2Aubry Tardivel (UNIL: University of Lausanne)H-Index: 41
Last. Jürg Tschopp (UNIL: University of Lausanne)H-Index: 153
view all 5 authors...
The signaling intermediates that activate inflammasomes have remained elusive. Tschopp and co-workers now describe that a thioredoxin-binding protein is a reactive oxygen species–regulated component of the NLRP3 inflammasome.
Summary: Gout is an arthritis characterized by elevated uric acid in the bloodstream. In this condition, crystals of uric acid are formed and accumulate in the synovial fluids. Crystal deposition leads to acute inflammation, which is associated with the spontaneous resolution of the disease. Recent studies have led to significant advances in the understanding of the basic biology of crystal-mediated inflammation. Uric acid has been identified as a danger signal that triggers a cytosolic sensor, ...
#1Oana Popa-Nita (Laval University)H-Index: 5
#2Paul H. Naccache (Laval University)H-Index: 32
Monosodium urate (MSU) crystals are among the most potent pro-inflammatory stimuli and an innate immune inflammatory response to the crystal surface is intimately involved in the pathology of gouty arthritis. The responses of human neutrophils to MSU crystals represent an integral part of this innate response and a key component of the acute inflammatory response associated with gout. A significant, though incomplete, body of information concerning the implication of human neutrophils in MSU cry...
#1Monica Guma (UCSD: University of California, San Diego)H-Index: 33
#2Lisa Ronacher (UCSD: University of California, San Diego)H-Index: 7
Last. Maripat Corr (UCSD: University of California, San Diego)H-Index: 69
view all 6 authors...
Objective Interleukin-1β (IL-1β) is a key cytokine linked to the pathogenesis of acute arthritis. Caspase 1, neutrophil elastase, and chymase all process proIL-1β to its biologically active form. This study was undertaken to examine the potential contributions of each of these proteases in experimental models of inflammatory arthritis. Methods Caspase 1–deficient (Casp1−/−) and wild-type (WT) mice were tested for their response to arthritogenic K/BxN serum transfer for induction of arthritis or ...
Cited By167
#1Rafaela Cunha Matosinhos (UFOP: Universidade Federal de Ouro Preto)H-Index: 1
#2Juliana Pantaleão Bezerra (UFOP: Universidade Federal de Ouro Preto)
Last. Dênia Antunes Saúde-Guimarães (UFOP: Universidade Federal de Ouro Preto)H-Index: 14
view all 9 authors...
Abstract null null Ethnopharmacological relevance null Coffea arabica is commonly known for its cardiotonic and neurotonic activities, but in some places’ folk medicine, like in Arabia and Africa, C. arabica is used to treat headache, migraine, the flu, anemia, oedema, asthenia, asthma, inflammation and wounds. null Aims of the study: The aims were to evaluate if the aqueous extracts of Coffea arabica, prepared from beans with different degrees of roasting, and their main chemical constituents c...
#1Camila Helena Barros (UFOP: Universidade Federal de Ouro Preto)H-Index: 2
#2Rafaela Cunha Matosinhos (UFOP: Universidade Federal de Ouro Preto)H-Index: 1
Last. Dênia Antunes Saúde-Guimarães (UFOP: Universidade Federal de Ouro Preto)H-Index: 14
view all 8 authors...
Abstract null null Ethnopharmacological relevance null Ethanolic extract of aerial parts from Lychnophora pinaster Mart. are used in traditional Brazilian medicine for treating pain, rheumatism and inflammation. null null null Aim of the study null Drugs for the treatment of gout present severe adverse effects, justifying the need to search for new therapeutic options. The aim of the present study was to evaluate the effects of the ethanolic extract of L. pinaster and its main constituents in ar...
#1Diego Pinto de Oliveira (UFMG: Universidade Federal de Minas Gerais)H-Index: 3
#2Eliana de Faria Garcia (UFMG: Universidade Federal de Minas Gerais)H-Index: 3
Last. Fernão Castro Braga (UFMG: Universidade Federal de Minas Gerais)H-Index: 23
view all 15 authors...
cis-Aconitic acid is a constituent from the leaves of Echinodorus grandiflorus, a medicinal plant traditionally used in Brazil to treat inflammatory conditions, including arthritic diseases. The present study aimed to investigate the anti-arthritic effect of cis-aconitic acid in murine models of antigen-induced arthritis and monosodium urate-induced gout. The possible underlying mechanisms of action was evaluated in THP-1 macrophages. Oral treatment with cis-aconitic acid (10, 30, and 90 mg/kg) ...
Lagotis brachystachya Maxim is a characteristic herb commonly used in Tibetan medicine. Tibetan medicine records it as an important medicine for the clinical treatment of "Yellow Water Disease", the symptoms of which are similar to that of arthritis. Our previous study showed that the flavonoid fraction extracted from Lagotis brachystachya could attenuate hyperuricemia. However, the effects of the active flavonoids on gouty arthritis remain elusive and the underlying mechanism is not understood....
#1Meng-Lin He (Nanjing University of Chinese Medicine)
#2Cheng Hu (Nanjing University of Chinese Medicine)H-Index: 5
Last. Weiqian Tian (Nanjing University of Chinese Medicine)H-Index: 1
view all 6 authors...
Acute gouty arthritis is a self-limiting inflammatory disease resulting from the deposition of monosodium urate (MSU) crystals. It has been shown that Gentiopicroside (GPS) possesses anti-inflammatory and analgesic functions. The aim of this study was to parse out whether GPS has an effect on acute gouty arthritis. We established an acute gouty arthritis model by the injection of MSU into the paw, and found that GPS relieves MSU-induced mechanical, thermal hyperalgesia, and paw swelling. Further...
#1Yifan Wang (Nanjing University of Chinese Medicine)H-Index: 3
#2Wen Zhu (Nanjing University of Chinese Medicine)H-Index: 2
Last. Yue Wang (Nanjing University of Chinese Medicine)H-Index: 2
view all 5 authors...
Activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome plays a crucial role in the inflammatory responses of monosodium urate (MSU) crystal-induced gouty arthritis. Therefore, the molecular basis of NLRP3 inflammasome is very valuable in developing potential therapeutic drugs for gout. Tetrahydropalmatine (THP), the main active component of the traditional Chinese medicinal herb Corydalis yanhusuo, has shown prominent anti-inflammatory and analgesic activities, but t...
#1Tiago H. Zaninelli (UEL: Universidade Estadual de Londrina)H-Index: 9
#2Victor Fattori (Boston Children's Hospital)H-Index: 23
Last. Waldiceu A. Verri (UEL: Universidade Estadual de Londrina)H-Index: 61
view all 3 authors...
The concept behind the resolution of inflammation has changed in the past decades from a passive to an active process, which reflects in novel avenues to understand and control inflammation-driven diseases. The time-dependent and active process of resolution phase is orchestrated by the endogenous biosynthesis of specialized pro-resolving lipid mediators (SPMs). Inflammation and its resolution are two forces in rheumatic diseases that affect millions of people worldwide with pain as the most com...
#1Chih-Chien Wang (NDMC: National Defense Medical Center)H-Index: 24
#2Jeng-Wei Lu (Singapore–MIT alliance)
Last. Chia-Chun Wu (NDMC: National Defense Medical Center)H-Index: 18
view all 10 authors...
Background and Objectives: Gouty arthritis is an acute inflammatory response caused by the precipitation of monosodium urate (MSU) crystals in joints. The triggering of MSU leads to increased production of inflammatory cytokines, such as interleukin-1β, which in turn lead to the formation of macromolecular complexes, referred to as inflammasomes. Thorough characterization of the NLRP3 inflammasome can be used as an indicator of an immune response against harmful stimuli. Cardamonin is a chalcone...
The pathogenesis of both diabetic retinopathy (DR) and rheumatoid arthritis (RA) has recently been considered to involve autoimmunity. Serum and synovial fluid levels of anti-type II collagen antibodies increase early after the onset of RA, thus inducing immune responses and subsequent hydrarthrosis and angiogenesis, which resemble diabetic macular edema and proliferative DR (PDR), respectively. We previously reported that DR is also associated with increased serum levels of anti-type II collage...
#1Hao-Fei Fan (HMU: Hainan Medical University)H-Index: 3
#2Fang Xingyue (HMU: Hainan Medical University)H-Index: 3
Last. Qibing Liu (HMU: Hainan Medical University)H-Index: 5
view all 9 authors...
Background null Gout is initiated by the precipitation of monosodium urate (MSU) crystals within the joints and soft tissues, and it can eventually cause acute or chronic arthritis. MSU crystals trigger, amplify, and maintain a strong inflammatory response through promoting proinflammatory activity. In this study, the therapeutic effects of Stephania hainanensis (S. hainanensis) total alkaloid (SHA) were tested and evaluated on MSU-induced acute gouty arthritis in a mouse model. null Methods nul...
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.