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8609360 
Journal Article 
Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus 
Goel, RR; Wang, X; O'Neil, LJ; Nakabo, S; Hasneen, K; Gupta, S; Wigerblad, G; Blanco, LP; Kopp, JB; Morasso, MI; Kotenko, SV; Yu, ZX; Carmona-Rivera, C; Kaplan, MJ 
2020 
1 
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
EISSN: 1091-6490 
117 
10 
5409-5419 
English 
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. 
IFNLR1 protein, mouse; Interferon Inducers; Interferon Type I; Receptors, Interferon; Toll-Like Receptor 7; interferon type III; Interferons; 9008-11-1; Imiquimod; P1QW714R7M; Index Medicus; autoimmunity; inflammation; interferon lambda; Receptors, Interferon -- genetics; Cell Line; Keratinocytes -- immunology; Inflammation -- pathology; Signal Transduction; Toll-Like Receptor 7 -- agonists; Inflammation -- immunology; Mice, Inbred C57BL; Mesangial Cells -- pathology; Toll-Like Receptor 7 -- physiology; Mesangial Cells -- immunology; Interferon Inducers -- pharmacology; B-Lymphocytes -- immunology; Animals; Imiquimod -- pharmacology; Mice, Mutant Strains; Gene Deletion; Mesangial Cells -- drug effects; Interferon Type I -- physiology; Keratinocytes -- pathology; Keratinocytes -- drug effects; Interferons -- pharmacology; Lupus Erythematosus, Systemic -- immunology; Lupus Erythematosus, Systemic -- pathology; Interferons -- physiology