Journal of Genetic Syndromes & Gene Therapy
Open Access

Abstract

The Allosteric CXCR1/2 Inhibitor DF2156A Improves Experimental Epidermolysis Bullosa Acquisita

Hirose M, Götz J, Recke A, Brandolini L, Zimmer D, Westermann J, Allegretti M, Moriconi A, Zillikens D, Kalies K and Ludwig RJ

Cytokines are an integral part of host response. However, aberrant cytokine responses are linked to chronic inflammatory diseases, including autoimmune bullous dermatoses (AIBD). AIBD are characterized by autoantibodies against cutaneous structural proteins, mucocutaneous tissue injury, and increased mortality. From the variety of differently expressed cytokines in AIBD, CXCR2 ligands, such as IL-8, seem to be promising therapeutic targets, as these have profound activating effects on neutrophils, which are indispensable for induction of skin lesions in different experimental models of AIBD. Therefore, we analyzed the contribution of CXCR2 ligands in experimental epidermolysis bullosa acquisita (EBA), an AIBD with autoimmunity to type VII collagen (COL7). We first evaluated the impact of the allosteric CXCR1/2 inhibitor DF2156A on neutrophil activation in vitro. The compound significantly reduced IL-8- and combined IL-8/immune complex-induced reactive oxygen species (ROS) release from neutrophils. Next, we noticed an increased expression of CXCL1 and CXCL2 in the skin of mice with experimental EBA. Interestingly, genetic (CXCR2-deficient mice) or pharmacologic inhibition (DF2156A) of CXCR2 function had only moderate and strain-dependent inhibitory effects in an antibody transfer model of EBA. In contrast, in a chronic, immunization-induced EBA mouse model, DF2156A showed profound therapeutic effects, which were comparable to high doses of systemic corticosteroids. Improvement of skin disease by blocking CXCR2 ligand function was independent of changes in circulating and tissue-bound anti-COL7 antibodies, excluding effects on adaptive immune cells. In summary, we here provide evidence that modulation of CXCR1/2 has therapeutic effects in EBA, a prototypical organ-specific autoimmune disease.