Tranilast directly targets NLRP 3 to treat inflammasome‐driven diseases

Abstract

The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases, but the medications targeting NLRP3 inflammasome are not available in clinic. Here, we show that tranilast (TR), an old anti‐allergic clinical drug, is a direct NLRP3 inhibitor. TR inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanismly, TR directly binds to the NACHT domain of NLRP3 and suppresses the assembly of NLRP3 inflammasome by blocking NLRP3 oligomerization. In vivo experiments show that TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3 inflammasome‐related human diseases, including gouty arthritis, cryopyrin‐associated autoinflammatory syndromes, and type 2 diabetes. Furthermore, TR is active ex vivo for synovial fluid mononuclear cells from patients with gout. Thus, our study identifies the old drug TR as a direct NLRP3 inhibitor and provides a potentially practical pharmacological approach for treating NLRP3‐driven diseases.

Inflammasomes contributing to inflammation in arthritis

“…Similar to MCC950, a compound called tranilast was found to bind to the NACHT domain of NLRP3, abolishing its ability to assemble into an inflammasome . This molecule is an analogue of a tryptophan metabolite that was initially identified as an anti‐allergy drug and is presently used in several inflammatory and autoimmune conditions .…”

“…RA studies in mice have shown that treatment with tranilast reduced disease in models of collagen‐induced arthritis and in arthritis induced by adjuvant and streptococcal cell wall products in rats . Its mode of action is still unclear and may not involve inhibition of NLRP3 ATPase activity . Tranilast has very low adverse effects; therefore, if further studies demonstrate its efficacy and specificity at inhibiting NLRP3, its repositioning in inflammasomopathies could be of great interest and may provide a new therapeutic tool for treating complex diseases with NLRP3 involvement.…”

“…17 Similar to MCC950, a compound called tranilast was found to bind to the NACHT domain of NLRP3, abolishing its ability to assemble into an inflammasome. 154 This molecule is an analogue of a tryptophan metabolite that was initially identified as an anti-allergy drug and is presently used in several inflammatory and autoimmune conditions. 155 RA studies in mice have shown that treatment with tranilast reduced disease in models of collagen-induced arthritis 156,157 and in arthritis induced by adjuvant and streptococcal cell wall products in rats.…”

“…158 Its mode of action is still unclear and may not involve inhibition of NLRP3 ATPase activity. 154 Tranilast has very low adverse effects; therefore, if further studies demonstrate its efficacy and specificity at inhibiting NLRP3, its repositioning in inflammasomopathies could be of great interest and may provide a new therapeutic tool for treating complex diseases with NLRP3 involvement.…”

Carnosol inhibits inflammasome activation by directly targeting HSP90 to treat inflammasome-mediated diseases

“…Thus, the NLRP3 inflammasome contributes to the development of several human diseases, including gout, Alzheimer's disease, enteritis and liver disease 4,8,20,21 . In recent years, several molecular compounds, including MCC950, OLT1177, Bay 11-7082, β-hydroxybutyrate glyburide, parthenolide, sulforaphane, glycyclamide, isoliquiritigenin and tranilast [22][23][24][25] , have been shown to have clear inhibitory effect on the NLRP3 inflammasome. MCC950, the most potent and specific inhibitor of NLRP3, has proven efficacy in many mouse models of NLRP3-driven diseases, such as colitis, NASH, Alzheimer's disease and other afflictions [26][27][28][29] .…”