Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 10, Pages 5409-5419Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1916897117
Keywords
interferon lambda; lupus; autoimmunity; skin; inflammation
Categories
Funding
- NIH/NIAMS Intramural Research Program [ZIAAR041199]
- NIH/National Institute of Diabetes and Digestive and Kidney Diseases IRP [ZO1 DK043308]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZICHL005904] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [ZIAAR041124, ZIAAR041199] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK043308] Funding Source: NIH RePORTER
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Type III IFN lambdas (IFN-7 lambda) 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-lambda, in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-lambda, protein is increased in murine lupus and IFN-lambda, receptor (tinWO 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-lambda, 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.
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