Bortezomib inhibits NLRP3 inflammasome activation and NF-ΚB pathway to reduce psoriatic inflammation

The abnormal activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain -containing protein 3 (NLRP3) inflammasome plays an important role in the pathogenesis of psoriasis. Accord-ingly, the inhibition of NLRP3 inflammasome may be an effective strategy for psoriasis treatment. However, the NLRP3 inflammasome inhibitors are not available in the clinic. Repurposing FDA-approved drugs is a highly attractive way for identifying new drugs. Here, proteasome inhibitor bortezomib, a marketed drug for treating multiple myeloma, was found to specifically inhibit NLRP3 inflammasome activation at nanomolar concentra-tions. Mechanistically, bortezomib did not inhibit reactive oxygen species generation, ion efflux, NLRP3 oligo-merization, and NLRP3-ASC interactions. Bortezomib reduced ASC oligomerization and ASC speck formation. In addition, bortezomib inhibited the activity of the core subunit beta 5i in the immunoproteasome and reduced beta 5i binding to NLRP3. Bortezomib reduced the production of interleukin-1 beta and attenuated the severity of skin le-sions in the imiquimod-induced psoriatic mouse model. Thus, bortezomib is a potential therapeutic drug for psoriasis. Our study also revealed that beta 5i may be an indirect target for regulating NLRP3 inflammasome acti-vation and treating psoriasis and other NLRP3 inflammasome-related diseases.

Automated summary

The abnormal activation of NLRP3 inflammasome is important in the pathogenesis of psoriasis. Bortezomib, a marketed drug for treating multiple myeloma, specifically inhibits NLRP3 inflammasome activation and may be a potential therapeutic drug for psoriasis.