T-lymphocyte-specific knockout of IKK-2 or NEMO induces T_h17 cells in an experimental nephrotoxic nephritis mouse...

Experimental nephrotoxic serum nephritis (NTN) is a model for T-cell-mediated human rapid progressive glomerulonephritis. T-cell receptor stimulation involves intracellular signaling events that ultimately lead to the activation of transcription factors, such as NF-κB. We explored the involvement of the NF-κB components IKK-2 and NEMO in NTN, by using cell-specific knockouts of IKK-2 and NEMO in CD4⁺ T lymphocytes. Our results demonstrate that although the course of disease was not grossly altered in CD4xIKK2^Δ and CD4xNEMO^Δ animals, renal regulatory T cells were significantly reduced and T helper (T_h)1 and T_h17 cells significantly increased in both knockout mouse groups. The expression of the renal cytokines and chemokines IL-1β, CCL-2, and CCL-20 was also significantly altered in both knockout mice. Lymphocyte transcriptome analysis confirmed the increased expression of T_h17-related cytokines in spleen CD4⁺ T cells. Moreover, our array data demonstrate an interrupted canonical NF-κB pathway and an increased expression of noncanonical NF-κB pathway-related genes in nephritic CD4xNEMO^Δ mice, highlighting different downstream effects of deletion of IKK-2 or NEMO in T lymphocytes. We propose that better understanding of the role of IKK-2 and NEMO in nephritis is essential for the clinical application of kinase inhibitors in patients with glomerulonephritis.-Guo, L., Huang, J., Chen, M., Piotrowski, E., Song, N., Zahner, G., Paust, H.-J., Alawi, M., Geffers, R., Thaiss, F. T-lymphocyte-specific knockout of IKK-2 or NEMO induces T_h17 cells in an experimental nephrotoxic nephritis mouse model.