Abstract
c-Jun N-terminal protein kinase 1 (JNK1) is involved in multiple biological processes but its implication in inflammatory skin diseases is still poorly defined. Herein, we studied the role of JNK1 in the context of Aldara®-induced skin inflammation. We observed that constitutive ablation of JNK1 reduced Aldara®-induced acanthosis and expression of inflammatory markers. Conditional deletion of JNK1 in myeloid cells led to reduced skin inflammation, a finding that was associated with impaired Aldara®-induced inflammasome activation in vitro. Next, we evaluated the specific role of JNK1 in epidermal cells. We observed reduced Aldara®-induced acanthosis despite similar levels of inflammatory markers. Transcriptomic and epigenomic analysis of keratinocytes revealed the potential involvement of JNK1 in the EGFR signaling pathway. Finally, we show that inhibition of the EGFR pathway reduced Aldara®-induced acanthosis. Taken together, these data indicate that JNK1 plays a dual role in the context of psoriasis by regulating the production of inflammatory cytokines by myeloid cells and the sensitivity of keratinocytes to EGFR ligands. These results suggest that JNK1 could represent a valuable therapeutic target in the context of psoriasis.
Highlights
Psoriasis is a chronic disease of unsolved pathogenesis that affects skin and joints in 1–3% of the general population
In order to determine the role of Jun N-terminal protein kinase 1 (JNK1) signaling pathway in skin inflammation, we evaluated the sensitivity of Mapk8-/- mice to repeated topical applications of Aldara®, a classical model that shares many features with human psoriasis (Figure 1B)
Aldara® treatment strongly enhanced expression of cytokines, chemokines (Cxcl1) and anti-microbial peptides (S100a9) in the skin of Mapk8+/+ mice. Induction of these inflammatory genes was strongly reduced in Aldara®-treated Mapk8-/- mice in comparison to their WT counterpart (Figure 1G). These results indicate that JNK1 represents an important signaling pathway in the context of Aldara®-induced skin inflammation
Summary
Psoriasis is a chronic disease of unsolved pathogenesis that affects skin and joints in 1–3% of the general population It arises in genetically susceptible hosts in response to ill-defined environmental triggers and is characterized by inflamed and scaly skin lesions and can be complicated by arthritis [1]. IL-17 stimulates keratinocytes and dermal fibroblasts leading to the expression of multiple antimicrobial peptides and chemokines that recruit and activate inflammatory cells [3]. Both TNF and IL-23/IL-17 axes represent major therapeutic targets that have dramatically changed the management of psoriasis and psoriatic arthritis [2]
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