Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus.
Rishi Raj GoelXinghao WangLiam J O'NeilShuichiro NakaboKowser HasneenSarthak GuptaGustaf WigerbladLuz P BlancoJeffrey B KoppMaria I MorassoSergei V KotenkoZu-Xi YuCarmelo Carmona-RiveraMariana J KaplanPublished in: Proceedings of the National Academy of Sciences of the United States of America (2020)
Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-λ protein is increased in murine lupus and IFN-λ receptor (Ifnlr1) deficiency significantly reduces immune cell activation and associated organ damage in the skin and kidneys without effects on autoantibody production. Single-cell RNA sequencing in mouse spleen and human peripheral blood revealed that only mouse neutrophils and human B cells are directly responsive to this cytokine. Rather, IFN-λ activates keratinocytes and mesangial cells to produce chemokines that induce immune cell recruitment and promote tissue inflammation. These data provide insights into the immunobiology of SLE and identify type III IFNs as important factors for tissue-specific pathology in this disease.
Keyphrases
- systemic lupus erythematosus
- immune response
- dendritic cells
- disease activity
- type iii
- single cell
- oxidative stress
- endothelial cells
- high glucose
- toll like receptor
- induced apoptosis
- inflammatory response
- rna seq
- drug induced
- cystic fibrosis
- machine learning
- staphylococcus aureus
- cell proliferation
- pseudomonas aeruginosa
- big data
- endoplasmic reticulum stress
- smoking cessation
- candida albicans
- protein protein
- binding protein
- cell cycle arrest