Interleukin-17 Cytokines Are Critical in Development of Fatal Lupus Glomerulonephritis

• Published in: Immunity (Cambridge, Mass.) Mass.), 2012-12, Vol.37 (6), p.1104-1115
• Main Authors: Pisitkun, Prapaporn, Ha, Hye-Lin, Wang, Hongshan, Claudio, Estefania, Tivy, Caitlyn C., Zhou, Hua, Mayadas, Tanya N., Illei, Gabor G., Siebenlist, Ulrich
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Autoantibodies - biosynthesis; Autoantibodies - immunology; Autoimmune diseases; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Chemotaxis, Leukocyte - immunology; Disease Models, Animal; Germinal Center - immunology; Germinal Center - metabolism; Glomerular Basement Membrane - immunology; Immune system; Interleukin-17 - genetics; Interleukin-17 - physiology; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Lupus; Lupus Nephritis - genetics; Lupus Nephritis - immunology; Lupus Nephritis - mortality; Lupus Nephritis - pathology; Mice; Mice, Knockout; Mortality; Protein Binding; Receptors, IgG - deficiency; Receptors, IgG - genetics; Receptors, Interleukin-17 - immunology; Receptors, Interleukin-17 - metabolism; Signal Transduction
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2012.08.014

Systemic lupus erythematosus is a potentially fatal autoimmune disease. Although interleukin-17 (IL-17) has been linked to human lupus and mouse models of this disease, it has not been addressed whether this cytokine plays a critical role in fatal lupus pathology. Here we have demonstrated that increased production of IL-17 cytokines and their signaling via the adaptor protein CIKS (a.k.a. Traf3ip2, Act1) critically contributed to lethal pathology in an FcgammaR2b-deficient mouse model of lupus. Mice lacking IL-17 and especially those lacking CIKS showed greatly improved survival and were largely protected from development of glomerulonephritis. Importantly in this model, potential effects of IL-17 cytokines on antibody production could be distinguished from critical local contributions in kidneys, including recruitment of neutrophils and monocytes. These findings provide the proof of principle that signaling by IL-17 family cytokines mediated via CIKS presents promising therapeutic targets for the treatment of systemic lupus erythematosus, especially in cases with kidney involvement. [Display omitted] ► IL-17 cytokines/CIKS are critical for fatal lupus nephritis in FcgR2b KO mice ► Loss of IL-17 cytokine signaling in B cells fails to prevent glomerulonephritis ► IL-17 cytokines promote GC formation but are not required for autoantibodies ► IL-17 cytokines promote inflammatory cell infiltration and NET formation in kidneys