Abstract
BackgroundInterleukin-17A (IL17A) is a proinflammatory cytokine critically involved in autoimmune diseases, and monoclonal antibodies of IL17A have been approved for clinical treatment of psoriasis. However, a usable psoriatic animal model has been always required for preclinical evaluation of IL17A antagonists. Imiquimod (IMQ)-induced psoriasis model is widely used in fundamental research, but it’s not able to accurately show anti-psoriatic effect of IL17A antagonists with conventional modelling condition.ResultsOn female C57BL/6 mice, with optimization on the usage of IMQ, positive control reagent and anti-mIL17A antibody, a 7-day model with proper testing window, acceptable disease severity as well as high repeatability was developed, and the efficacy of IL17A antagonist can be objectively evaluated by several qualitative and quantitative indices. Meanwhile, we validated the detailed involvement of IL17A signaling in disease progression, confirmed that the expression levels of IL17A and its related cytokines were induced by IMQ application, and its downstream cytokines can be inhibited by IL17A antagonist treatment. In further study, we revealed that IL17A was transient induced by IMQ and directly caused downstream signaling activation. This finding on the kinetical change of IL17A signaling will manifest the pharmacokinetics-pharmacodynamics investigation of IL17A antagonists.ConclusionsOur work presents the application of a convenient psoriatic animal model in the research and development of IL17A antagonists, meanwhile providing extra evidence for understanding IL17A’s role in the progression of IMQ-induced psoriasis model, which manifest the research and development of IL17A antagonists.
Highlights
Interleukin-17A (IL17A) is a proinflammatory cytokine critically involved in autoimmune diseases, and monoclonal antibodies of IL17A have been approved for clinical treatment of psoriasis
Involvement of IL17A in inflammation and autoimmune disease has been widely illustrated since its discovery on 2005, and abnormal expressions of IL17A are found in development of several diseases including psoriasis
Optimization of imiquimod-induced psoriasis model for illustrating the efficacy of IL17A antagonization Several researches have proved that consecutive 7-day application of 62.5 mg/mice/day IMQ cream on back skin induces significant psoriasis-like pathological change in C57BL/6 mice [18, 22, 24], we confirmed in our laboratory this modelling condition induced classical pathological changes including the formation of white scales, thicken-induced skin wrinkle, as well as distinct redness on day 5 (Fig. 1a); blocking IL17A pathway with anti-IL-17A antibody (10 mg/kg, 3 times/week) didn’t affect the disease process
Summary
Interleukin-17A (IL17A) is a proinflammatory cytokine critically involved in autoimmune diseases, and monoclonal antibodies of IL17A have been approved for clinical treatment of psoriasis. Imiquimod (IMQ)-induced psoriasis model is widely used in fundamental research, but it’s not able to accurately show anti-psoriatic effect of IL17A antagonists with conventional modelling condition. Psoriasis is the first indication approved for clinical usage of anti-IL17A monoclonal antibody [12], and so far, psoriasis is still considered the very first indication for research of most IL17A antagonists. Imiquimod (IMQ) is a ligand for Toll-like receptors 7/8 which activates macrophages, monocytes and dendritic cells, by directly administrating on mice skin, it induces significant psoriasis-like skin damage [15, 16], and this model has been well-studied and widely used in fundamental research [17]. There are differences existing in both mechanism and clinical feature between IMQinduced psoriasis in mice and human psoriasis [18], in consideration of its acute and severe characters in disease progression, the usage of IMQ model is restricted in preclinical drug development
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