P-Glycoprotein induction in Plasma cells drives treatment resistance in Lupus Nephritis via IL-17/TAK-1/C/EBP-β pathway 2258946

Abstract

Abstract Introduction Despite advances in lupus nephritis (LN) management, many patients fail to respond to first-line therapy or relapse after remission. Overexpression of P-glycoprotein (p-gp) on Plasma cells (PCs) and T-helper 17 lymphocytes (Th17) cells may contribute to disease activity and drug-resistant phenotype in LN. Objective Evaluation of role of IL-17 mediated pathway (IL-17/TAK-1/C/EBP-β pathway) in upregulation of P-gp expression in PCs and lymphocytes of LN and their contribution in the refractoriness to standard treatment. Methods The expression of P-gp on PCs and Th17 cells from LN patients were analysed. U266B1 plasma cells were treated with rIL-17, rIL-6+sIL-6R, or their inhibitors–anti-IL-6 plus anti-IL-17, IL-17 plus (5Z)-7-oxozeaenol (TAK-1 inhibitor), or IL-17 plus ST101 (C/EBP-β inhibitor). Plasma concentrations of NGAL, IL-17, IL-6, TNF-α, CXCL12, and CXCL13 were quantified by ELISA. Results 49 LN patients (refractory n = 11; active n = 20; inactive n = 18) and 15 healthy controls were studied. Frequencies of CD38+CD138+ PCs, and P-gp+ PCs, Th17, P-gp+Th17, were significantly elevated in refractory and active LN compared with inactive LN and controls, which decreased after 3 months of standard therapy. IL-17, IL-6, TNF-α, CXCL12, and NGAL levels were elevated in plasma and declined post-treatment (P < 0.001). In vitro, IL-6 + IL-17 stimulation induced P-gp expression in plasma cell line, In pre treatment strategy, expression of P-gp was significantly suppressed by anti-IL-6 + anti-IL-17, or by IL-17 inhibition combined with (5Z)-7-oxozeaenol or ST101.While, in the post treatment strategy, expression of P-gp was not significantly decreased when treated with anti-IL-6 + anti-IL-17 or IL-17 inhibition combined with (5Z)-7-oxozeaenol or ST101. Conclusion IL-17 upregulates P-gp via the IL17/TAK-1/C/EBP-β pathway, contributing to therapeutic refractoriness in LN. Targeting IL-17 signaling axis represent a novel therapeutic approach for refractory LN. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)