1. IL-26 Confers Proinflammatory Properties to Extracellular DNA.
- Author
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Poli C, Augusto JF, Dauvé J, Adam C, Preisser L, Larochette V, Pignon P, Savina A, Blanchard S, Subra JF, Chevailler A, Procaccio V, Croué A, Créminon C, Morel A, Delneste Y, Fickenscher H, and Jeannin P
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Autoantigens immunology, Cells, Cultured, Computer Simulation, DNA immunology, Extracellular Space metabolism, Extracellular Traps metabolism, Female, Humans, Interleukins immunology, Male, Membrane Proteins metabolism, Middle Aged, Myocytes, Smooth Muscle physiology, Protein Binding, Protein Conformation, Young Adult, Autoantigens metabolism, DNA metabolism, Glomerulonephritis immunology, Inflammation Mediators metabolism, Interleukins metabolism, Kidney pathology, Monocytes immunology
- Abstract
In physiological conditions, self-DNA released by dying cells is not detected by intracellular DNA sensors. In chronic inflammatory disorders, unabated inflammation has been associated with a break in innate immune tolerance to self-DNA. However, extracellular DNA has to complex with DNA-binding molecules to gain access to intracellular DNA sensors. IL-26 is a member of the IL-10 cytokine family, overexpressed in numerous chronic inflammatory diseases, in which biological activity remains unclear. We demonstrate in this study that IL-26 binds to genomic DNA, mitochondrial DNA, and neutrophil extracellular traps, and shuttles them in the cytosol of human myeloid cells. As a consequence, IL-26 allows extracellular DNA to trigger proinflammatory cytokine secretion by monocytes, in a STING- and inflammasome-dependent manner. Supporting these biological properties, IL-10-based modeling predicts two DNA-binding domains, two amphipathic helices, and an in-plane membrane anchor in IL-26, which are structural features of cationic amphipathic cell-penetrating peptides. In line with these properties, patients with active autoantibody-associated vasculitis, a chronic relapsing autoimmune inflammatory disease associated with extensive cell death, exhibit high levels of both circulating IL-26 and IL-26-DNA complexes. Moreover, in patients with crescentic glomerulonephritis, IL-26 is expressed by renal arterial smooth muscle cells and deposits in necrotizing lesions. Accordingly, human primary smooth cells secrete IL-26 in response to proinflammatory cytokines. In conclusion, IL-26 is a unique cationic protein more similar to a soluble pattern recognition receptor than to conventional cytokines. IL-26 expressed in inflammatory lesions confers proinflammatory properties to DNA released by dying cells, setting up a positive amplification loop between extensive cell death and unabated inflammation., (Copyright © 2017 by The American Association of Immunologists, Inc.)
- Published
- 2017
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