Innate immune processes are central in the development of the chronic inflammatory skin disease psoriasis. Studying stimulation of keratinocytes, monocytes, and dendritic cells by type I interferons or ligation of Toll-like receptors 1/2, 2/6, or 7, but not 7/8, resulted in enhanced surface expression and secretion of CXC chemokine ligand (CXCL) 16. The corresponding CXC chemokine receptor 6 was expressed on neutrophils whose recruitment into skin is important, especially in early psoriatic disease. Using the recently developed technique real-time deformability cytometry demonstrated that CXCL16 and IL-8 decreased the stiffness and enhanced deformation of neutrophils facilitating transmigration through vessel wall. In addition, CXCL16 potently induced migration of neutrophils and enhanced the chemotactic effect of IL-8. The positive feedback loop was supported by IL-8 enhancing CXCL16 production of neutrophils. Blocking of CXCL16 expression by effective treatment of psoriasis patients with tumor necrosis factor-α blockers further supported the pathogenic role of this chemokine. In summary, the data link innate immune stimulation to CXCL16 upregulation and neutrophil infiltration into skin. CXCL16 could therefore represent a potent future target for treatment of psoriasis.

Nucleic acid accumulation in repeat expansion disease poses multiple challenges to cellular integrity. Myotonic dystrophy type 2 (DM2) results from large CCTG repeats in the CNBP gene leading to myopathy and an increased prevalence of autoimmunity. Here, we observed that DM2 patients exhibited a type-I interferon signature in blood and cultured fibroblasts. RNA repeat accumulation was prevalent in the cytosol of DM2 patient fibroblasts, facilitating repeat-associated non-AUG translation. The ensuing chronic endoplasmic reticulum (ER) stress response led to an ATF6-controlled induction of type-I IFN dependent on the cGAS/STING pathway. Recapitulating chronic ER stress in the monocytic THP-1 cell line revealed its dependence on mitochondrial DNA (mtDNA). Correspondingly, mitochondrial stress and cytosolic leakage of mtDNA was observed in DM2 patient fibroblasts. Altogether, our study demonstrates a novel mechanism by which large repeat expansions cause chronic ER and mitochondrial stress and induce a type-I interferon response that predisposes to autoimmunity. Keywords: ER stress, ATF6, Autoimmunity, type I IFN, repeat expansions

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