1. C/EBPδ Mediates Immunity to Renal Autoinflammatory Disorders in a Stage-specific Manner.
- Author
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Dey I, Li Y, Taylor TC, Peroumal D, Asada N, Panzer U, Biswas PS, Sterneck E, and Gaffen SL
- Subjects
- Animals, Mice, Humans, Interleukin-17 immunology, Interleukin-17 metabolism, Disease Models, Animal, Lipocalin-2 genetics, Lipocalin-2 metabolism, Lipocalin-2 immunology, Aristolochic Acids toxicity, Kidney immunology, Kidney pathology, Glomerulonephritis immunology, Glomerulonephritis pathology, Autoantibodies immunology, Mice, Inbred C57BL, Th17 Cells immunology, Signal Transduction immunology, CCAAT-Enhancer-Binding Protein-delta genetics, Mice, Knockout
- Abstract
Kidney disease represents a major medical and economic burden for which improved treatments are urgently needed. Emerging data have implicated Th17 cells and IL-17 signaling in the underlying pathogenesis of autoantibody-induced glomerulonephritis (AGN). However, the downstream transduction pathways mediated by IL-17 in autoimmunity are not well defined. In this article, we show that CCAAT/enhancer-binding protein (C/EBP) δ is elevated in kidney biopsies from multiple manifestations of human AGN. C/EBPδ is similarly upregulated in a mouse model of anti-glomerular basement membrane protein-mediated kidney disease, and Cebpd-/- mice were fully refractory to disease. Although C/EBPδ is expressed in a variety of cell types, C/EBPδ was required only in the radioresistant compartment to drive GN pathology. C/EBPδ induced expression of several IL-17-induced kidney injury markers and cytokines implicated in disease, including Il6 and Lcn2. Because mouse AGN models do not progress to fibrosis, we employed a nephrotoxic injury model using aristolochic acid I to assess the contribution of the IL-17-C/EBPδ pathway to renal fibrotic events. Surprisingly, deficiency of either C/EBPδ or the IL-17 receptor caused kidney fibrosis to be enhanced. Thus, C/EBPδ and IL-17 play divergent and apparently stage-specific roles in the pathogenesis of kidney disease., (Copyright © 2024 by The American Association of Immunologists, Inc.)
- Published
- 2024
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