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.