Imiquimod-Induced Psoriasis in Mice Depends on the IL-17 Signaling of Keratinocytes

Abstract

The pathology of psoriasis strongly depends on IL-17A. Monoclonal antibodies blocking either the cytokine or its receptor are among the most efficient treatments for psoriatic patients. Keratinocytes can be activated upon exposure to IL-17A and tumor necrosis factor-a and secrete secondary cytokines and chemokines in the inflamed skin. In psoriasis and its imiquimod-induced mouse model, a strong skin infiltration of neutrophils and inflammatory monocytes can be observed. However, to date, it is not clear how exactly those cellular populations are attracted to the skin and how they contribute to the pathogenesis of the disease. To define the crucial cell type responding to IL-17 and initiating the downstream pathology in psoriasis-like dermatitis, we used mice specifically lacking the IL-17 receptor (IL-17RA) in different cell types. Deletion of IL-17RA in T cells or myeloid had no impact on disease development. Only deletion of this receptor in keratinocytes reflected the full-body deletion of IL-17RA, resulting in strongly reduced dermatitis development. Imiquimod treatment of those IL-17 signalingedeficient mice maintained high monocytic infiltration but failed to attract neutrophils into the skin. We conclude that keratinocytes are a critical cellular target for IL-17Aemediated neutrophil attraction and psoriasis development.

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

“…In a similar way, the role of the cytoskeleton regulator Arp2/3 complex was evaluated by transcriptomics of an Arpc4 knockout mouse strain to investigate psoriasis-specific features [207]. In the field of psoriasis research, Imiquimod (IMQ)-induced dermatitis is a widely used murine model which mainly acts via TLR7/8 agonism [208] and largely depends on IL-17 signaling [209][210][211]. Swindell et al investigated its validity in a large study with different mouse strains and gender dependency and compared transcriptomic data with psoriasis and other human inflammatory skin disease profiles.…”

Psoriasis Pathogenesis: Keratinocytes Are Back in the Spotlight

“…Psoriasis can be conceptualized as an exaggerated physiological response to epithelial damage or wounding, and we now know that keratinocytes are essential and central players in this response (Figure 1). Like most informative studies, the results reported by Moos et al (2019) allow for speculations and suggest new questions. Could a future therapeutic strategy aim to neutralize IL-17 signaling selectively in keratinocytes?…”

“…One of the best described types of T cell-mediated inflammation leading to a chronic inflammatory skin disease is type 17 immune-driven induction of psoriasis. Moos and colleagues (2019) now provide convincing evidence that this inflammatory cascade is critically dependent on keratinocytes (Moos et al, 2019). Moos and colleagues (2019) investigated several murine models in which the IL-17 receptor component IL-17RA was deleted in distinct cell types, including T cells, neutrophils, macrophages, or keratinocytes, to determine which cell types were critical IL-17 responders in skin.…”

ZnO NPs delay the recovery of psoriasis-like skin lesions through promoting inflammation and keratinocyte apoptosis via nuclear translocation of phosphorylated NF-κB p65 and cysteine deficiency

“…In psoriasis, IL-1 is likely to initiate the in ammatory response and cause dysfunction of keratinocytes; furthermore, TNF-α, IL-1 and IL-6 derived from dysregulated keratinocytes amplify the in ammatory response through promoting the differentiation of myeloid dendritic cells [19,25,26]. IL-17A and IL-22 released by activated lymphocytes mediate chronic in ammation in psoriasis [21,[27][28][29]. In psoriasis, high expression of COX2 is associated with a persistent in ammatory response [19,30].…”