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.

Highlights

  • 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

  • We report in this article that IL-26: 1) exhibits several features of cell-penetrating peptide (CPP) designed for DNA transfection and, 2) allows myeloid cells to be activated by extracellular DNA in an inflammasome-dependent and stimulator of IFN genes (STING)-dependent manner

  • This property is supported by its unique biochemical and structural features, which are similar to the ones of cell-penetrating [40] and antimicrobial peptides [55], such as the cathelicidin LL-37 [13, 14]

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Summary

Introduction

The synergistic effect of IL-26 and DNA on proinflammatory cytokine production by monocytes was observed with genomic DNA and with mtDNA ( released by dying cells [36]) and NETs. Whereas NETs alone (used at 10–300 ng/ml NETs-associated DNA content) did not induce detectable IL-6 (Fig. 1A), addition of IL-26 resulted in a huge secretion of IL-6, dependent on the doses of NETs DNA (Fig. 1A). These results show that IL-26 synergizes with extracellular self-DNA to induce proinflammatory cytokine secretion by human myeloid cells.

Results
Conclusion
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