Serum amyloid A induces interleukin-33 expression through an IRF7-dependent pathway

Area of Science:

• Immunology
• Molecular Biology

Background:

• Interleukin-33 (IL-33) is an IL-1 family cytokine and nuclear alarmin.
• IL-33 is constitutively expressed in barrier tissues but its induction in monocytes/macrophages is less understood.
• Monocytes and macrophages are key cytokine-producing innate immune cells.

Purpose of the Study:

• To investigate the mechanisms of IL-33 induction in monocytes and macrophages.
• To identify the role of serum amyloid A (SAA) in IL-33 expression.
• To elucidate the transcription factors involved in SAA-mediated IL-33 induction.

Main Methods:

• Treatment of human monocytes and mouse macrophages with SAA.
• Analysis of Il33 gene transcription and protein accumulation.
• Reporter assays using progressive deletions of the IL-33 promoter.
• Identification of transcription factor binding sites (IRF7).
• Silencing of IRF7 expression and assessment of Il33 induction.
• Investigation of protein-protein interactions (SAA, TLR2, IRF7, TRAF6).

Main Results:

• SAA induces IL-33 expression and nuclear accumulation in monocytes and macrophages.
• Toll-like receptor 2 (TLR2) is essential for SAA-induced IL-33 expression.
• A specific region (-277/-257) of the IL-33 promoter is critical for SAA-stimulated activity.
• Interferon regulatory factor 7 (IRF7) binds to the IL-33 promoter and is required for SAA-induced IL-33 expression.
• SAA promotes an interaction between IRF7 and TNF receptor-associated factor 6 (TRAF6).

Conclusions:

• Serum amyloid A (SAA) is a potent inducer of IL-33 in monocytes and macrophages.
• TLR2 and IRF7 are critical components of the signaling pathway for SAA-induced IL-33 expression.
• IRF7 acts as a key transcription factor regulating Il33 gene activation by SAA in myeloid cells.