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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,3,10]]},"abstract":"<jats:p>Type III IFN lambdas (IFN-\u03bb) 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-\u03bb in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-\u03bb protein is increased in murine lupus and IFN-\u03bb 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-\u03bb 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.<\/jats:p>","DOI":"10.1073\/pnas.1916897117","type":"journal-article","created":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T20:25:33Z","timestamp":1582575933000},"page":"5409-5419","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":135,"title":["Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus"],"prefix":"10.1073","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1715-5191","authenticated-orcid":false,"given":"Rishi R.","family":"Goel","sequence":"first","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghao","family":"Wang","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam J.","family":"O\u2019Neil","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichiro","family":"Nakabo","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kowser","family":"Hasneen","sequence":"additional","affiliation":[{"name":"Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarthak","family":"Gupta","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustaf","family":"Wigerblad","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8468-6518","authenticated-orcid":false,"given":"Luz P.","family":"Blanco","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey B.","family":"Kopp","sequence":"additional","affiliation":[{"name":"Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria I.","family":"Morasso","sequence":"additional","affiliation":[{"name":"Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei V.","family":"Kotenko","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103;"},{"name":"Center for Cell Signaling, Rutgers New Jersey Medical School, Newark, NJ 07103;"},{"name":"Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zu-Xi","family":"Yu","sequence":"additional","affiliation":[{"name":"Pathology Core Facility, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmelo","family":"Carmona-Rivera","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2968-0815","authenticated-orcid":false,"given":"Mariana J.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,2,24]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1056\/NEJMra1100359","article-title":"Systemic lupus erythematosus","volume":"365","author":"Tsokos G. C.","year":"2011","unstructured":"G. C. Tsokos, Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110\u20132121 (2011).","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1084\/jem.20021553","article-title":"Interferon and granulopoiesis signatures in systemic lupus erythematosus blood","volume":"197","author":"Bennett L.","year":"2003","unstructured":"L. Bennett ., Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711\u2013723 (2003).","journal-title":"J. Exp. Med."},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"5459","DOI":"10.4049\/jimmunol.1002795","article-title":"Type I interferon in the pathogenesis of lupus","volume":"192","author":"Crow M. K.","year":"2014","unstructured":"M. K. Crow, Type I interferon in the pathogenesis of lupus. J. Immunol. 192, 5459\u20135468 (2014).","journal-title":"J. Immunol."},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1002\/art.37824","article-title":"Sifalimumab, a human anti-interferon-\u03b1 monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study","volume":"65","author":"Petri M.","year":"2013","unstructured":"M. Petri ., Sifalimumab, a human anti-interferon-\u03b1 monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study. Arthritis Rheum. 65, 1011\u20131021 (2013).","journal-title":"Arthritis Rheum."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1136\/annrheumdis-2014-206090","article-title":"A phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-\u03b1) in patients with systemic lupus erythematosus (ROSE)","volume":"75","author":"Kalunian K. C.","year":"2016","unstructured":"K. C. Kalunian ., A phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-\u03b1) in patients with systemic lupus erythematosus (ROSE). Ann. Rheum. Dis. 75, 196\u2013202 (2016).","journal-title":"Ann. Rheum. Dis."},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1136\/annrheumdis-2015-208562","article-title":"Sifalimumab, an anti-interferon-\u03b1 monoclonal antibody, in moderate to severe systemic lupus erythematosus: A randomised, double-blind, placebo-controlled study","volume":"75","author":"Khamashta M.","year":"2016","unstructured":"M. Khamashta .; CD1067 study investigators, Sifalimumab, an anti-interferon-\u03b1 monoclonal antibody, in moderate to severe systemic lupus erythematosus: A randomised, double-blind, placebo-controlled study. Ann. Rheum. Dis. 75, 1909\u20131916 (2016).","journal-title":"Ann. Rheum. 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