In gout, monosodium urate (MSU) crystals trigger IL-1β production, but exactly how MSU crystals mediate this process is not well understood. A new study suggests that MSU crystals can stimulate inflammation by interacting with transforming growth factor-β-activated kinase 1 (TAK1; also known as MAP3K7), which regulates the expression of several pro-inflammatory cytokines including IL-1β and TNF.
“Studies so far have emphasized the primary role of the NLRP3 inflammasome in MSU crystal-induced inflammation,” explains corresponding author Salah Ahmed. “This is the first study to identify the molecular and post-translational mechanisms triggered by MSU crystals in macrophages and to propose TAK1 as a potential therapeutic target for gout.”
In vitro studies in THP-1 macrophages and human monocyte-derived macrophages revealed that MSU crystals could activate proteins involved downstream in the IL-1β signalling pathway (including TAK1) without the need for IL-1β itself. Further in vitro investigations showed that MSU crystals also modulated protein ubiquitination and the expression of deubiquitination enzymes, thereby accelerating pro-inflammatory cytokine production.
In THP-1 macrophages, administration of the TAK1 inhibitor 5Z-7-oxozeaenol (5ZO) suppressed MSU crystal-induced production of pro-inflammatory cytokines, including IL-1β. Molecular dynamics simulations revealed that urate molecules can directly bind to TAK1 and arrest the kinase in an activated state, potentially explaining the effects of MSU crystals on TAK1.
In mice with MSU crystal-induced inflammation (a model for gout), administration of 5ZO prior to disease onset inhibited inflammation and reduced disease severity to a level comparable with that induced by the urate-lowering therapy febuxostat.
“urate molecules can directly bind to TAK1 and arrest the kinase in an activated state”
“Our plan is to extend these findings into macrophages from patients with gout to further validate the mechanism in a clinical population,” says Ahmed. “These findings might also be applied in other autoimmune diseases where IL-1β has a central role,” he suggests.
Singh, A. K. et al. Suppression of monosodium urate crystal-induced inflammation by inhibiting TGF-β-activated kinase 1-dependent signaling: role of the ubiquitin proteasome system. Cell. Mol. Immunol. https://doi.org/10.1038/s41423-019-0284-3 (2019)