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.
Highlights
NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple tumor necrosis factor (TNF) family members, including BAFF, TNF-related weak inducer of apoptosis (TWEAK), CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE)
NIK SMI1 potently inhibited anti-LTβR-induced nuclear p52 levels in these cells, while it had no effect on canonical signaling as measured by TNF alpha-induced nuclear relA levels (Fig. 1e, Supplementary Fig. 1b)
We investigated whether the strong effects on plasmablasts and autoantibody production, which were not observed with BAFF blockade, might be due to effects of NIK inhibition on T-cells, perhaps through perturbation of OX40 signaling
Summary
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). 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. NIK deficient mice, or mice that express a variant of NIK protein (aly mutation) unable to associate with IKKα, cannot activate the non-canonical NF-κB pathway These mutant mice are severely immune-deficient as a result of disrupted splenic and lymphoid organ architecture[19], and reduced or missing lymph nodes[19,20,21]. Similar phenotypes have been detected in patients with mutations in MAP3K14 or NFKB2 that prevent non-canonical signaling[29,30]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
