Inhibitor of NFκB Kinase Subunit 2 Blockade Hinders the Initiation but Aggravates the Progression of Crescentic GN

Abstract

The NFκB transcription factor family facilitates the activation of dendritic cells (DCs) and CD4(+) T helper (Th) cells, which are important for protective adaptive immunity. Inappropriate activation of these immune cells may cause inflammatory disease, and NFκB inhibitors are promising anti-inflammatory drug candidates. Here, we investigated whether inhibiting the NFκB-inducing kinase IKK2 can attenuate crescentic GN, a severe DC- and Th cell-dependent kidney inflammatory disease. Prophylactic pharmacologic IKK2 inhibition reduced DC and Th cell activation and ameliorated nephrotoxic serum-induced GN in mice. However, therapeutic IKK2 inhibition during ongoing disease aggravated the nephritogenic immune response and disease symptoms. This effect resulted from the renal loss of regulatory T cells, which have been shown to protect against crescentic GN and which require IKK2. In conclusion, although IKK2 inhibition can suppress the induction of nephritogenic immune responses in vivo, it may aggravate such responses in clinically relevant situations, because it also impairs regulatory T cells and thereby, unleashes preexisting nephritogenic responses. Our findings argue against using IKK2 inhibitors in chronic GN and perhaps, other immune-mediated diseases.

T‐lymphocyte–specific knockout of IKK‐2 or NEMO induces T h 17 cells in an experimental nephrotoxic nephritis mouse model

“…At the transcriptional level, analysis of the T-cell transcriptome identified the aberrant regulation of gene expression by NF-kB in the differentiation of T h 17 cells, which was balanced with that of T reg cells. Our data suggest that NF-kB plays a major role in mediating T-cell activation and that noncanonical NF-kB signaling is critical for T h 17-cell induction in our current model, whereas T reg cells critically depend on the canonical NF-kB pathway activation as had been shown in the data in our previous study (20). The T h 17 cell immune function depends on fine tuning of canonical NF-kB signaling.…”

“…S1). As expected, increased NF-kB activation was found in the kidneys of all groups with no significant difference after the induction of NTN, as shown by Gotot et al (20). The induction of NTN significantly increased the albumin:creatinine ratio in all groups on d 2 and 9.…”

“…We have shown previously that total kidney NF-kB was activated after the induction of NTN (20), which was also confirmed in CD4xIKK2 D and CD4xNEMO D mice and may explain why no significant functional and morphologic changes were observed at 10 d after NTN induction. Our results do not exclude, however, that functional or morphologic changes may occur at later time points and influence the long-term outcome in these mice.…”

“…We and others have demonstrated NF-kB activation in glomerulonephritis, and in 2016 we demonstrated that IKK-2 inhibition before NTN induction attenuated the nephritogenic T h cell response (20). Therefore, genetically modified mice were used to examine the effects of IKK-2 or NEMO deletion, specifically in T lymphocytes, in the experimental NTN model.…”

“…A study published from our laboratory by Gotot et al (20) showed that systemic IKK-2 inhibition after the induction of the disease increased renal injury in the NTN model and that activated cytotoxic T lymphocytes were resistant to IKK-2 inhibition because of other pathways-in particular, nuclear factor of activated T-cell signaling (21). NF-kB activation was demonstrated by our group after ischemia-reperfusion kidney injury, and more Th17 cells were found in ischemic CD4xNEMO D mice but not in CD4xIKK2 D mice (22).…”