PMID- 21952942
OWN - NLM
STAT- MEDLINE
DCOM- 20120913
LR  - 20161125
IS  - 1529-0131 (Electronic)
IS  - 0004-3591 (Linking)
VI  - 64
IP  - 2
DP  - 2012 Feb
TI  - NLRP3 inflammasome-mediated neutrophil recruitment and hypernociception depend on 
      leukotriene B(4) in a murine model of gout.
PG  - 474-84
LID - 10.1002/art.33355 [doi]
AB  - 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 B(4) (LTB(4) ) 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-1beta (IL-1beta), 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, LTB(4) activity, cytokine 
      (IL-1beta, 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-1beta/MyD88-dependent manner. LTB(4) was produced rapidly after injection of 
      MSU crystals, and this was necessary for caspase 1-dependent IL-1beta production and 
      consequent release of CXCR2-acting chemokines in vivo. In vitro, macrophages 
      produced LTB(4) after MSU crystal injection, and LTB(4) was relevant in the MSU 
      crystal-induced maturation of IL-1beta. Mechanistically, LTB(4) 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 LTB(4) in driving NLRP3 inflammasome 
      activation in response to MSU crystals, both in vitro and in vivo.
CI  - Copyright (c) 2012 by the American College of Rheumatology.
FAU - Amaral, Flavio A
AU  - Amaral FA
AD  - Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
FAU - Costa, Vivian V
AU  - Costa VV
FAU - Tavares, Livia D
AU  - Tavares LD
FAU - Sachs, Daniela
AU  - Sachs D
FAU - Coelho, Fernanda M
AU  - Coelho FM
FAU - Fagundes, Caio T
AU  - Fagundes CT
FAU - Soriani, Frederico M
AU  - Soriani FM
FAU - Silveira, Tatiana N
AU  - Silveira TN
FAU - Cunha, Larissa D
AU  - Cunha LD
FAU - Zamboni, Dario S
AU  - Zamboni DS
FAU - Quesniaux, Valerie
AU  - Quesniaux V
FAU - Peres, Raphael S
AU  - Peres RS
FAU - Cunha, Thiago M
AU  - Cunha TM
FAU - Cunha, Fernando Q
AU  - Cunha FQ
FAU - Ryffel, Bernhard
AU  - Ryffel B
FAU - Souza, Daniele G
AU  - Souza DG
FAU - Teixeira, Mauro M
AU  - Teixeira MM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Carrier Proteins)
RN  - 0 (Cytokines)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Reactive Oxygen Species)
RN  - 1HGW4DR56D (Leukotriene B4)
RN  - 268B43MJ25 (Uric Acid)
RN  - EC 3.4.22.36 (Caspase 1)
SB  - IM
CIN - Nat Rev Rheumatol. 2011 Dec;7(12):684. PMID: 22025121
MH  - Animals
MH  - Carrier Proteins/*metabolism
MH  - Caspase 1/metabolism
MH  - Cytokines/metabolism
MH  - Gout/chemically induced/immunology/*metabolism
MH  - Hyperalgesia/immunology/*metabolism
MH  - Inflammasomes/immunology/*metabolism
MH  - Inflammation/immunology/metabolism
MH  - Interleukin-1beta/metabolism
MH  - Leukotriene B4/immunology/*metabolism
MH  - Macrophages/immunology/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - NLR Family, Pyrin Domain-Containing 3 Protein
MH  - Neutrophil Infiltration/*physiology
MH  - Neutrophils/immunology/*metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Synovial Membrane/immunology/metabolism
MH  - Uric Acid/pharmacology
EDAT- 2011/09/29 06:00
MHDA- 2012/09/14 06:00
CRDT- 2011/09/29 06:00
PHST- 2011/09/29 06:00 [entrez]
PHST- 2011/09/29 06:00 [pubmed]
PHST- 2012/09/14 06:00 [medline]
AID - 10.1002/art.33355 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2012 Feb;64(2):474-84. doi: 10.1002/art.33355.