title: Transmembrane TNF-α is sufficient for articular inflammation and hypernociception in a mouse model of gout.
abstract: Gout manifests as recurrent episodes of acute joint inflammation and pain due to the deposition of monosodium urate (MSU) crystals within the affected tissue in a process dependent on NLRP3 inflammasome activation. The synthesis, activation, and release of IL-1β are crucial for MSU-induced inflammation. The current study evaluated the mechanism by which TNF-α contributed to MSU-induced inflammation. Male C57BL/6J or transgenic mice were used in this study and inflammation was induced by the injection of MSU crystals into the joint. TNF-α was markedly increased in the joint after the injection of MSU. There was inhibition in the infiltration of neutrophils, production of CXCL1 and IL-1β, and decreased hypernociception in mice deficient for TNF-α or its receptors. Pharmacological blockade of TNF-α with Etanercept or pentoxyfylline produced similar results. Mechanistically, TNF-α blockade resulted in lower amounts of IL-1β protein and pro-IL-1β mRNA transcripts in joints. Gene-modified mice that express only transmembrane TNF-α had an inflammatory response similar to that of WT mice and blockade of soluble TNF-α (XPro™1595) did not decrease MSU-induced inflammation. In conclusion, TNF-α drives expression of pro-IL-1β mRNA and IL-1β protein in experimental gout and that its transmembrane form is sufficient to trigger MSU-induced inflammation in mice.
authors.affiliation: Immunopharmacology Lab, Department of Biochemistry and Immunology, Federal University of Minas, Gerais, Brazil.
authors.forename: Flávio A
authors.initials: FA
authors.lastname: Amaral
authors.affiliation: Immunopharmacology Lab, Department of Biochemistry and Immunology, Federal University of Minas, Gerais, Brazil.
authors.forename: Leandro F S
authors.initials: LF
authors.lastname: Bastos
authors.affiliation: Immunopharmacology Lab, Department of Biochemistry and Immunology, Federal University of Minas, Gerais, Brazil.
authors.forename: Thiago H C
authors.initials: TH
authors.lastname: Oliveira
authors.affiliation: Department of Microbiology, Federal University of Minas, Gerais, Brazil.
authors.forename: Ana C F
authors.initials: AC
authors.lastname: Dias
authors.affiliation: Immunopharmacology Lab, Department of Biochemistry and Immunology, Federal University of Minas, Gerais, Brazil.
authors.forename: Vívian L S
authors.initials: VL
authors.lastname: Oliveira
authors.affiliation: Department of Microbiology, Federal University of Minas, Gerais, Brazil.
authors.forename: Lívia D
authors.initials: LD
authors.lastname: Tavares
authors.affiliation: Department of Microbiology, Federal University of Minas, Gerais, Brazil.
authors.forename: Vivian V
authors.initials: VV
authors.lastname: Costa
authors.affiliation: Immunopharmacology Lab, Department of Biochemistry and Immunology, Federal University of Minas, Gerais, Brazil.
authors.forename: Izabela
authors.initials: I
authors.lastname: Galvão
authors.affiliation: Department of General Biology, Federal University of Minas, Gerais, Brazil.
authors.forename: Frederico M
authors.initials: FM
authors.lastname: Soriani
authors.affiliation: Xencor, Monrovia, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Szymkowski
authors.affiliation: Molecular Immunology and Embryology, Centre National de la Recherche Scientifique, Orléans, France.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: Department of Microbiology, Federal University of Minas, Gerais, Brazil.
authors.forename: Danielle G
authors.initials: DG
authors.lastname: Souza
authors.affiliation: Immunopharmacology Lab, Department of Biochemistry and Immunology, Federal University of Minas, Gerais, Brazil.
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006073:Gout / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D006930:Hyperalgesia / Q000209:etiology*; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D007719:Knee Joint; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010812:Physical Stimulation; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014527:Uric Acid / Q000009:adverse effects / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D014527:Uric Acid
keywords: Cytokines; Gout; Inflammation; Innate immune; Neutrophils; TNFIntroduction