NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus

• Published in: Nature communications Vol. 9; no. 1; pp. 179 - 14
• Main Authors: Brightbill, Hans D, Suto, Eric, Blaquiere, Nicole, Ramamoorthi, Nandhini, Sujatha-Bhaskar, Swathi, Gogol, Emily B, Castanedo, Georgette M, Jackson, Benjamin T, Kwon, Youngsu C, Haller, Susan, Lesch, Justin, Bents, Karin, Everett, Christine, Kohli, Pawan Bir, Linge, Sandra, Christian, Laura, Barrett, Kathy, Jaochico, Allan, Berezhkovskiy, Leonid M, Fan, Peter W, Modrusan, Zora, Veliz, Kelli, Townsend, Michael J, DeVoss, Jason, Johnson, Adam R, Godemann, Robert, Lee, Wyne P, Austin, Cary D, McKenzie, Brent S, Hackney, Jason A, Crawford, James J, Staben, Steven T, Alaoui Ismaili, Moulay H, Wu, Lawren C, Ghilardi, Nico
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 12.01.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Antibodies; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Binding sites; Cell Proliferation - drug effects; Cell Survival - drug effects; Chronic conditions; Clinical trials; Cytokine TWEAK - metabolism; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Disease Models, Animal; Gene expression; Gene Expression - drug effects; Humans; In Vitro Techniques; Inflammation - genetics; Interleukin-12 Subunit p40 - drug effects; Interleukin-12 Subunit p40 - immunology; Kidney - drug effects; Kidney - immunology; Kidney - pathology; Kinases; Ligands; Lupus; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - immunology; Lupus Nephritis - immunology; Lupus Nephritis - pathology; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred NZB; Molecular Targeted Therapy; Mutation; NF-kappaB-Inducing Kinase; Pathogenesis; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Proteins; Proteinuria; Proteinuria - immunology; Receptors, OX40 - metabolism; Signal Transduction; Signaling; Spleen; Spleen - drug effects; Spleen - immunology; Systemic lupus erythematosus; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tumor necrosis factor-TNF
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02672-0

NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE. Furthermore, NIK inhibition also affects T cell parameters in the spleen and proinflammatory gene expression in the kidney, which may be attributable to inhibition of OX40 and TWEAK signaling, respectively. As a consequence, NIK inhibition results in improved survival, reduced renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition is a potential therapeutic approach for SLE.