Abstract
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.
Highlights
Autoimmune diseases have become a significant health burden, as the prevalence has continuously increased over the last decades [1], patients suffer from a high morbidity and mortality [2], and therapeutic options are mainly still limited to general immunosuppressive therapies
For both resting and immune complexactivated neutrophils, the maximal reactive oxygen species (ROS) release was achieved with an IL-8 concentration of 50 ng/ml, which declined if concentrations above 50 ng/ml were used in figure 1A and 1B)
We recently reported that mice affected by immunization-induced Epidermolysis bullosa acquisita (EBA) gain less weight compared to age-matched control mice [23]
Summary
Autoimmune diseases have become a significant health burden, as the prevalence has continuously increased over the last decades [1], patients suffer from a high morbidity and mortality [2], and therapeutic options are mainly still limited to general immunosuppressive therapies. F(ab’) fragments of anti-COL7 IgG or anti-COL7 IgY failed to induce clinical disease in mice, while injection of rabbit, human or murine anti-COL7 IgG was shown to induce skin blisters [9]. This blister formation requires binding of Fc gamma RIV to autoantibodies deposited along the dermal-epidermal junction [10]. In this model, histological examination of skin biopsies from common gamma chain or Fc gamma RIV-deficient mice are completely devoid of dermal leukocyte infiltration [10]. In highly purified neutrophil preparations, IL-1ra, IL-8, M-CSF, GRO-α, MIP-1 and MIP-1β have been described to be released upon activation [11,12,13]
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