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.

The cGAS/STING Pathway Detects Streptococcus pneumoniae but Appears Dispensable for Antipneumococcal Defense in Mice and Humans

“…Moreover, we show that expression of the hypomorphic HAQ variant of STING dramatically reduces S. pneumoniae-induced type I IFN responses, but that it appears to have no major influence on the susceptibility of nonvaccinated individuals toward pneumococcal pneumonia or on disease severity. We speculate that the divergent effect of type I IFN versus STING deficiencies on pneumococcal infections can be explained by the capacity of cGAS/STING to also regulate the production of other mediators in addition to type I IFNs (53,54). Indeed, STING-dependent signaling has been shown to activate various transcription factors, such as IRF3, NF-B, and STAT6 (21,53).…”

Biological Effects of IL-26 on T Cell–Mediated Skin Inflammation, Including Psoriasis

“…While immunofluorescence staining of skin sections of hIL-26Tg mice indicated that IL-26 was produced by CD4-positive cells as well as other cell types, the cells involved may differ in the IMQ-induced psoriasis model from psoriasis patients (Figure 3b, 3d). In addition to Th17 cells, other IL-26eproducing cells have been identified recently (Che et al, 2014(Che et al, , 2017Corvaisier et al, 2012;Poli et al, 2017). In the skin lesions of psoriatic patients, IL-17 is produced not only from CD4 þ T cells, but also from CD8 þ T cells and gd T cells (Golden et al, 2013;Matos et al, 2017).…”

NETs By-products and Extracellular DNA May Play a Key Role in COVID-19 Pathogenesis: Incidence on Patient Monitoring and Therapy

“…However, the re-entry process of self-DNA in host cells is a biological feature that clearly differentiates NETs and mononucleosomes. (This process has been well reviewed by Poli et al, 2017) Nucleic acids appear to be the main source of DAMPs, and stimulate Pattern Recognition Receptors (PRR) to induce inflammation (Elkon et al, 2019). The location of nucleic acid sensing receptors can be conveniently divided into endosomal and cytosolic.…”