BACKGROUND: GPR15 has been implicated in the pathogenesis of T cell-driven inflammation of the skin and the gut. Expression levels of the GPR15 ligand GPR15 L are increased in psoriatic skin and considered as potential biomarker for the treatment response to anti-IL-17 antibody therapies. However, the significance of the GPR15 L/GPR15 for the pathogenesis of psoriasis and the mechanisms regulating GPR15 L expression are still elusive. OBJECTIVE: To determine the significance of GPR15 signaling in mouse models of psoriasis. METHODS: We addressed the role of the GPR15 L/GPR15 in the Aldara™-induced psoriasiform dermatitis (AIPD) and the IL-23-induced dermatitis model. In both models, we charted the expression levels of GPR15 L in the skin and assessed the significance of GPR15 L/GPR15 by examining Gpr15-/- mice. RESULTS: GPR15 L levels were increased in the AIPD, but not in the IL-23-induced dermatitis model. Deficiency in Gpr15 did not alter the course of disease neither in the AIPD, nor in the IL-23-induced dermatitis model. In neither model, deficiency in Gpr15 modulated disease on the histopathological or the molecular level. Despite the induction of GPR15 L in the AIPD model, GPR15+ cells did not accumulate in the skin. CONCLUSION: GPR15 L expression is induced in psoriasiform dermatitis, but the activation of the IL-23/IL-17 axis alone is not sufficient for its induction. This restricts the potential use of GPR15 L levels as biomarker for the treatment response to anti-IL-17 antibody therapy. Our results leave a significant role of GPR15 in the pathogenesis of psoriasiform dermatitis rather unlikely. Hence, GPR15 L probably modulates psoriasiform dermatitis via GPR15-independent pathways.
BACKGROUND:GPR15 has been implicated in the pathogenesis of T cell-driven inflammation of the skin and the gut. Expression levels of the GPR15 ligand GPR15 L are increased in psoriatic skin and considered as potential biomarker for the treatment response to anti-IL-17 antibody therapies. However, the significance of the GPR15 L/GPR15 for the pathogenesis of psoriasis and the mechanisms regulating GPR15 L expression are still elusive. OBJECTIVE: To determine the significance of GPR15 signaling in mouse models of psoriasis. METHODS: We addressed the role of the GPR15 L/GPR15 in the Aldara™-induced psoriasiform dermatitis (AIPD) and the IL-23-induced dermatitis model. In both models, we charted the expression levels of GPR15 L in the skin and assessed the significance of GPR15 L/GPR15 by examining Gpr15-/- mice. RESULTS:GPR15 L levels were increased in the AIPD, but not in the IL-23-induced dermatitis model. Deficiency in Gpr15 did not alter the course of disease neither in the AIPD, nor in the IL-23-induced dermatitis model. In neither model, deficiency in Gpr15 modulated disease on the histopathological or the molecular level. Despite the induction of GPR15 L in the AIPD model, GPR15+ cells did not accumulate in the skin. CONCLUSION:GPR15 L expression is induced in psoriasiform dermatitis, but the activation of the IL-23/IL-17 axis alone is not sufficient for its induction. This restricts the potential use of GPR15 L levels as biomarker for the treatment response to anti-IL-17 antibody therapy. Our results leave a significant role of GPR15 in the pathogenesis of psoriasiform dermatitis rather unlikely. Hence, GPR15 L probably modulates psoriasiform dermatitis via GPR15-independent pathways.
Authors: Lifeng Xiong; Joseph W Dean; Zheng Fu; Kristen N Oliff; John W Bostick; Jian Ye; Zongming E Chen; Marcus Mühlbauer; Liang Zhou Journal: Sci Immunol Date: 2020-06-12