title: IL-26 Confers Proinflammatory Properties to Extracellular DNA.
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.
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.|Laboratoire d'Immunologie et Allergologie, CHU Angers, 49000 Angers, France.
authors.forename: Caroline
authors.identifier: 0000-0003-1170-5586
authors.initials: C
authors.lastname: Poli
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.|Service de Néphrologie-Dialyse-Transplantation, CHU Angers, 49000 Angers, France.
authors.forename: Jean François
authors.identifier: 0000-0003-1498-2132
authors.initials: JF
authors.lastname: Augusto
authors.affiliation: Institut de Cancérologie de l'Ouest Paul Papin, 49000 Angers, France.
authors.forename: Jonathan
authors.identifier: 0000-0002-2565-8066
authors.initials: J
authors.lastname: Dauvé
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Adam
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Preisser
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Larochette
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Pignon
authors.affiliation: Roche SAS Scientific Partnerships, 92100 Boulogne Billancourt, France.
authors.forename: Ariel
authors.initials: A
authors.lastname: Savina
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.|Laboratoire d'Immunologie et Allergologie, CHU Angers, 49000 Angers, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Blanchard
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.|Service de Néphrologie-Dialyse-Transplantation, CHU Angers, 49000 Angers, France.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Subra
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.|Laboratoire d'Immunologie et Allergologie, CHU Angers, 49000 Angers, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Chevailler
authors.affiliation: INSERM, CNRS, Université d'Angers, 49000 Angers, France.|Laboratoire de Biochimie et Génétique, CHU Angers, 49000 Angers, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.affiliation: Laboratoire d'Histopathologie-Cytopathologie, Département de Pathologie Cellulaire et Tissulaire, CHU Angers, 49000 Angers, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Croué
authors.affiliation: Service de Pharmacologie et d'Immunoanalyse, Commissariat à l'Energie Atomique Saclay, iBiTec-S, 91190 Gif sur Yvette, France; and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Créminon
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.|Institut de Cancérologie de l'Ouest Paul Papin, 49000 Angers, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Morel
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France.|Laboratoire d'Immunologie et Allergologie, CHU Angers, 49000 Angers, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Delneste
authors.affiliation: Institute for Infection Medicine, Christian Albrecht University of Kiel and University Medical Center Schleswig-Holstein, 24000 Kiel, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fickenscher
authors.affiliation: CRCINA, INSERM, Université de Nantes, Université d'Angers, LabEx IGO, 49000 Angers, France; pascale.jeannin@univ-angers.fr.|Laboratoire d'Immunologie et Allergologie, CHU Angers, 49000 Angers, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Jeannin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D003198:Computer Simulation; D004247:DNA / Q000276:immunology / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D065206:Extracellular Traps / Q000378:metabolism; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D007668:Kidney / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D011485:Protein Binding; D011487:Protein Conformation; D055815:Young Adult; D000099197:STING Protein
chemical_list: D001324:Autoantigens; D004247:DNA; D018836:Inflammation Mediators; D007378:Interleukins; D008565:Membrane Proteins; C406767:IL26 protein, human; C532857:STING1 protein, human; D000099197:STING Protein