Leucine enhances the cGAS-STING-NLRP3 pathway in autoimmune thyroiditis

Area of Science:

• Immunology
• Metabolomics
• Genetics

Background:

• Branched-chain amino acids (BCAAs) are crucial for immune regulation.
• The role of BCAAs in autoimmune thyroiditis (AIT) pathogenesis is largely unknown.
• This study investigates the causal link between BCAAs and AIT.

Purpose of the Study:

• To determine the causal relationship between BCAAs and AIT using Mendelian randomization.
• To explore the role of BCAAs in the cGAS-STING-NLRP3 pathway in vitro.
• To investigate leucine's specific impact on AIT pathogenesis.

Main Methods:

• Two-sample Mendelian randomization (MR) was employed to assess causality.
• In vitro experiments utilized lipopolysaccharide (LPS)-induced thyroid follicular cells (TFCs).
• Investigated the effects of BCAAs and leucine deprivation on inflammatory markers and cellular pathways.

Main Results:

• BCAAs were identified as a pathogenic factor for AIT (OR = 4.960, P = 0.007).
• Leucine (Leu) significantly worsened AIT by increasing inflammatory cytokines (TNF-α, IL-6), cellular damage, and oxidative stress.
• Leu activated Sestrin2/mTOR and cGAS-STING-NLRP3 pathways, while Leu deprivation inhibited these pathways.

Conclusions:

• Genetically predicted leucine levels show a potential causal effect on AIT.
• Leucine exacerbates AIT through the Sestrin2/mTOR and cGAS-STING-NLRP3 signaling pathways.
• Leucine deprivation presents a potential therapeutic strategy for AIT.