Sensing soluble uric acid by Naip1-Nlrp3 platform

Area of Science:

• Immunology
• Molecular Biology
• Evolutionary Biology

Background:

• Uric acid (UA) is a purine degradation product capable of initiating immune responses.
• Humans lack uricase, the enzyme for UA cleavage, leading to its accumulation.
• Soluble UA (sUA) can induce interleukin-1β (IL-1β) in murine macrophages.

Purpose of the Study:

• To investigate if the Naip1-Nlrp3 inflammasome recognizes soluble uric acid (sUA).
• To explore the role of Naip1 in mediating sUA-induced inflammation in human macrophages.

Main Methods:

• Structural modeling predictions.
• Transcriptome and functional analyses in human macrophages.
• Pharmacological and genetic inhibition of Nlrp3.
• Molecular interaction experiments.

Main Results:

• Murine Naip1 expression in human macrophages induced IL-1β expression, fatty acid production, and inflammation upon sUA stimulation.
• Nlrp3 inhibition reversed the sUA-induced inflammatory response.
• Molecular interaction studies confirmed direct binding between Naip1 and sUA.

Conclusions:

• Naip1 acts as a direct receptor for soluble uric acid (sUA).
• The Naip1-Nlrp3 inflammasome pathway mediates sUA-induced inflammation in human macrophages.
• Naip1 may represent the uric acid receptor lost during human evolution, offering potential therapeutic targets for hyperuricemia.