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12-01-2018 | Systemic lupus erythematosus | Article

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

Journal:
Nature Communications

Authors: Hans D. Brightbill, Eric Suto, Nicole Blaquiere, Nandhini Ramamoorthi, Swathi Sujatha-Bhaskar, Emily B. Gogol, Georgette M. Castanedo, Benjamin T. Jackson, Youngsu C. Kwon, Susan Haller, Justin Lesch, Karin Bents, Christine Everett, Pawan Bir Kohli, Sandra Linge, Laura Christian, Kathy Barrett, Allan Jaochico, Leonid M. Berezhkovskiy, Peter W. Fan, Zora Modrusan, Kelli Veliz, Michael J. Townsend, Jason DeVoss, Adam R. Johnson, Robert Godemann, Wyne P. Lee, Cary D. Austin, Brent S. McKenzie, Jason A. Hackney, James J. Crawford, Steven T. Staben, Moulay H. Alaoui Ismaili, Lawren C. Wu, Nico Ghilardi

Publisher: Nature Publishing Group UK

Abstract

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.

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