1. NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus.
- Author
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Brightbill HD, Suto E, Blaquiere N, Ramamoorthi N, Sujatha-Bhaskar S, Gogol EB, Castanedo GM, Jackson BT, Kwon YC, Haller S, Lesch J, Bents K, Everett C, Kohli PB, Linge S, Christian L, Barrett K, Jaochico A, Berezhkovskiy LM, Fan PW, Modrusan Z, Veliz K, Townsend MJ, DeVoss J, Johnson AR, Godemann R, Lee WP, Austin CD, McKenzie BS, Hackney JA, Crawford JJ, Staben ST, Alaoui Ismaili MH, Wu LC, and Ghilardi N
- Subjects
- Animals, B-Lymphocytes immunology, Cell Proliferation drug effects, Cell Survival drug effects, Cytokine TWEAK metabolism, Dendritic Cells drug effects, Dendritic Cells immunology, Disease Models, Animal, Gene Expression drug effects, Humans, In Vitro Techniques, Inflammation genetics, Interleukin-12 Subunit p40 drug effects, Interleukin-12 Subunit p40 immunology, Kidney immunology, Kidney pathology, Lupus Erythematosus, Systemic drug therapy, Lupus Nephritis immunology, Lupus Nephritis pathology, Mice, Mice, Inbred NZB, Molecular Targeted Therapy, Proteinuria immunology, Receptors, OX40 metabolism, Signal Transduction, Spleen drug effects, Spleen immunology, T-Lymphocytes immunology, NF-kappaB-Inducing Kinase, B-Lymphocytes drug effects, Kidney drug effects, Lupus Erythematosus, Systemic immunology, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, T-Lymphocytes drug effects
- 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.
- Published
- 2018
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