Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus

Area of Science:

• Immunology
• Autoimmunity
• Molecular Biology

Background:

• Type I interferons (IFN-I) are implicated in systemic lupus erythematosus (SLE) pathogenesis.
• The role of Type III interferons (IFN-λ) in SLE and other autoimmune diseases remains largely unexplored.
• IFN-λ are known mediators of immune responses at barrier surfaces.

Purpose of the Study:

• To investigate the role of IFN-λ in a mouse model of TLR7-induced lupus.
• To determine if IFN-λ contributes to immune dysregulation and tissue inflammation in SLE.
• To identify cell types directly responsive to IFN-λ in SLE.

Main Methods:

• Murine model of TLR7-induced lupus.
• Measurement of IFN-λ protein levels.
• Analysis of Ifnlr1 deficiency effects on immune cell activation and organ damage.
• Single-cell RNA sequencing of mouse spleen and human peripheral blood.

Main Results:

• IFN-λ protein levels are elevated in murine lupus.
• Ifnlr1 deficiency significantly reduces immune cell activation and organ damage (skin, kidneys) in lupus models.
• Autoantibody production remains unaffected by Ifnlr1 deficiency.
• Mouse neutrophils and human B cells are directly responsive to IFN-λ.
• IFN-λ activates keratinocytes and mesangial cells to produce chemokines, driving immune cell recruitment and inflammation.

Conclusions:

• IFN-λ plays a nonredundant role in immune dysregulation and tissue inflammation in a lupus model.
• IFN-λ contributes to tissue-specific pathology in SLE.
• Targeting IFN-λ pathways may offer a therapeutic strategy for SLE-related organ damage.