Transmembrane TNF-α is sufficient for articular inflammation and hypernociception in a mouse model of gout

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-1 beta are crucial for MSU-induced inflammation. The current study evaluated the mechanism by which TNF-alpha 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-alpha was markedly increased in the joint after the injection of MSU. There was inhibition in the infiltration of neutrophils, production of CXCL1 and IL-1 beta, and decreased hypernociception in mice deficient for TNF-alpha or its receptors. Pharmacological blockade of TNF-alpha with Etanercept or pentoxyfylline produced similar results. Mechanistically, TNF-alpha blockade resulted in lower amounts of IL-1 beta protein and pro-IL-1 beta mRNA transcripts in joints. Gene-modified mice that express only transmembrane TNF-alpha had an inflammatory response similar to that of WT mice and blockade of soluble TNF-alpha (XPro (TM) 1595) did not decrease MSU-induced inflammation. In conclusion, TNF-alpha drives expression of pro-IL-1 beta mRNA and IL-1 beta protein in experimental gout and that its transmembrane form is sufficient to trigger MSU-induced inflammation in mice.