The Inhibitory Effects of Alpha 1 Antitrypsin on Endosomal TLR Signaling Pathways.

Area of Science:

• Immunology
• Molecular Biology
• Rheumatology

Background:

• Endosomal toll-like receptors (TLRs) 7, 8, and 9 are implicated in systemic lupus erythematosus (SLE) pathogenesis.
• Proteolytic processing of these TLRs is essential for their signaling.
• Human alpha 1 antitrypsin (hAAT) is a protease inhibitor with known anti-inflammatory effects, but its impact on endosomal TLRs was unknown.

Purpose of the Study:

• To investigate the effect of hAAT on TLR7, TLR8, and TLR9 signaling pathways.
• To explore hAAT's potential as a therapeutic agent targeting TLR-mediated pathogenesis in SLE.

Main Methods:

• In vitro studies using dendritic cells (DCs) treated with hAAT and TLR agonists (TLR9 ligand, R848 for TLR7/8).
• Western blot analysis to assess cleaved TLR9 expression.
• In vivo studies using hAAT transgenic mice challenged with R848.

Main Results:

• hAAT inhibited TLR9-mediated DC activation, cytokine production, and interferon signature gene expression.
• hAAT reduced the expression of active (cleaved) TLR9 in DCs.
• hAAT also inhibited R848-induced TLR7/8 signaling in DCs and attenuated R848-induced pathogenesis in hAAT transgenic mice, including blocking key immune cell populations implicated in lupus.

Conclusions:

• hAAT effectively inhibits both TLR7/8 and TLR9 signaling pathways.
• hAAT demonstrates a novel mechanism of action by reducing the active form of TLR9.
• These findings support the potential clinical application of hAAT for treating SLE and other TLR-mediated inflammatory diseases.