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Abstract
The G protein-coupled receptor 15 (GPR15) has recently been highlighted as an important regulator of T cell trafficking into the gut under physiological and pathophysiological conditions. Additionally, circumstantial evidence has accumulated that GPR15 may also play a role in the regulation of chronic inflammation. However, the (patho)physiological significance of GPR15 has, in general, remained rather enigmatic. In the present study, we have addressed the role of GPR15 in the effector phase of autoantibody-mediated skin inflammation, specifically in the antibody transfer mouse model of bullous pemphigoid-like epidermolysis bullosa acquisita (BP-like EBA). Subjecting Gpr15−/− mice to this model, we have uncovered that GPR15 counteracts skin inflammation. Thus, disease was markedly aggravated in Gpr15−/− mice, which was associated with an increased accumulation of γδ T cells in the dermis. Furthermore, GPR15L, the recently discovered cognate ligand of GPR15, was markedly upregulated in inflamed skin. Collectively, our results highlight GPR15 as counter-regulator of neutrophilic, antibody-mediated cutaneous inflammation. Enhancing the activity of GPR15 may therefore constitute a novel therapeutic principle in the treatment of pemphigoid diseases, such as BP-like EBA.
Highlights
Evidence has accumulated that the G protein-coupled receptor 15 (GPR15) may modulate chronic inflammation
Wild-type and Gpr15−/− mice were subjected to the antibody transfer BP-like EBA mouse model and the course of disease was monitored for 14 days
By immunofluorescence staining of perilesional skin of wild-type and Gpr15−/− mice for IgG and C3, we subsequently demonstrated that both IgG and C3 were deposited at the dermal-epidermal junction (DEJ) in both groups, confirming the specificity of skin inflammation observed in our experiment (Figure 1C)
Summary
Evidence has accumulated that the G protein-coupled receptor 15 (GPR15) may modulate chronic inflammation. GPR15 is highly expressed on a population of IL-17-producing CD4+ T cells emerging in the peripheral blood of patients with ulcerative colitis or multiple sclerosis [3, 4]. It is induced on T cells of cigarette smokers, a behavior leading to a state of chronic systemic low-level inflammation [1,2,3,4]. The functional significance of the upregulation of GPR15 under these conditions has only been investigated in detail for the pathogenesis of gut inflammation.
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