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 TM 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.Keywords: Cytokines r Gout r Inflammation r Innate immune r Neutrophils r TNFIntroductionGout is an inflammatory arthropathy caused by deposition of uric acid crystals mainly in the joint and is characterized by localized inflammation and intense pain. This condition has a severe impact in the quality of life [1] and its incidence is rising [2]. Injection of MSU crystals in mice will activate in an Correspondence: Prof. Mauro M. Teixeira

Grape seed-derived procyanidins alleviate gout pain via NLRP3 inflammasome suppression

“…The intra-articular injection of MSU crystals induces the onset of pain-like behavior in mice [10, 32]. In accordance with the findings of a previous study, the mechanical pain threshold of mice decreased obviously and allodynia was induced after an intra-articular ankle injection of MSU crystals; this effect reached a maximum 8 h after injection and lasted 72 h in our study.…”

Hippocampal TNFα Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy

“…Although sTNFα is a major ligand for TNFR1, tmTNFα has been shown to induce inflammation and cytotoxicity through TNFR1 (Horiuchi et al, 2010). A recent study showed that tmTNFα was sufficient to cause inflammation in a gout model, and therefore, inhibition of sTNFα by XPro1595 did not provide beneficial effects (Amaral et al, 2016). Moreover, lymphotoxin (LTα3), formerly known as TNFβ, binds to both TNFRs (Tracey et al, 2008).…”

IL-17A neutralizing antibody regulates monosodium urate crystal-induced gouty inflammation

“…Leukocyte recruitment into the knee joint is a hallmark of gout inflammation and arthritis pathology [40,41]. Thus, based on previous results, we selected the most active doses (10μg) of IL-17Ab to test the modulation of leukocyte recruitment and activation.…”

“…All these processes are mainly related to activated neutrophils and macrophages which are responsible for the release of PGE2, IL-1β, TNF-α, and, activate nociceptor neuron and thereby producing pain [53,54,55]. Indeed, targeting IL-1β, TNF-α or PGE2 in rheumatic diseases reduce neutrophil recruitment and associated pain [40].…”