Early tissue responses in psoriasis to the antitumour necrosis factor-α biologic etanercept suggest reduced interleukin-17 receptor expression and signalling

Abstract

BACKGROUND Anti-TNF-α therapy has made a significant impact on the treatment of psoriasis. Despite being designed to neutralize TNF-α activity, the mechanism of action of these agents in the resolution of psoriasis remains unclear. OJECTIVES To better understand the mechanism of action of etanercept by examining very early changes in the lesional skin of psoriasis patients responding to etanercept. METHODS 20 chronic plaque psoriasis patients were enrolled and received 50mg etanercept twice weekly. Skin biopsies were obtained before treatment and on days 1, 3, 7 and 14 post-treatment. Skin mRNA expression was analysed by QRT-PCR and microarray; cytokine and phosphoprotein levels were assessed using multiplexed bead arrays. RESULTS In etanercept responders, we observed no significant changes in IL-17A, IL-22 and IFN-γ mRNA or protein in the first week of treatment; however, there was a 2.5-fold down-regulation of IL17RC mRNA (p<0.05) after day 1, accompanied by decreased ERK1/2 phosphorylation. Transcriptional analysis revealed genes suppressed by etanercept significantly overlapped with IL-17A-induced genes, and a marked overlap was also observed between the genes suppressed by etanercept and by the anti-IL17A therapy ixekizumab. Finally we show that TNF-α enhances the expression of IL-17RC and shRNA inhibition of IL-17R expression abrogates synergistic gene induction by TNF and IL17A. CONCLUSIONS These results suggest that the early responses of psoriasis plaques to etanercept may be due to decreased tissue responsiveness to IL-17A due to suppressed IL17RC expression in keratinocytes, blunting the strong synergy between TNF-α and IL-17, which contributes to the maintenance of psoriasis lesions.

IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis

“…Infliximab has been reported to have a rapid effect, with systemic inflammation and skin pustules starting to recede in as little as 2 days from the first infusion. In this context, the efficacy of infliximab likely stems from the rapid availability of the drug following infusion, and its inhibition of the synergy between TNF and multiple inflammatory cytokines including IL-36, IL-17A, IL-1β (26, 29, 43, 44). We detected increased IL-17A activity in GPP lesions using GSEA of microarray data (Figure 3) despite not being able to detect a significant increase in IL-17A transcripts by qRT-PCR (Figure 4); this discordance may be the result of the lack of sensitivity of the PCR assay for IL-17A in FFPE samples, contrasting with the ability of GSEA to detect the downstream effects of cytokines on transcriptional networks, or possibly similarities in IL-1/17/36-induced gene sets driving a perceived IL-17A signature in the data.…”

IL-36 Promotes Myeloid Cell Infiltration, Activation, and Inflammatory Activity in Skin

“…Many of the inflammatory mediators induced by IL-36 have been demonstrated to be over-expressed in psoriatic skin lesions including CCL3, CCL5, CXCL1, CXCL8, and CCL20 (5, 21, 22) suggesting that IL-36 may contribute to the chemokine environment of inflamed skin. Indeed, intradermal injection of recombinant murine IL-36α to mouse skin resulted in chemokine expression, leukocyte infiltration and inflammation (Figure 2).…”

Cytokines in psoriasis

“…In the time since, drugs targeting tumor necrosis factor (TNF)-α, interleukin (IL)-12/23, IL-17, IL-22, IL-23, granulocyte monocyte-colony stimulating factor (GM-CSF), as well as inhibitors of the Janus kinases (JAK1/2/3) downstream of a number of cytokine receptors, have reached the clinic or are currently in clinical trials [8]. Recently several technologies have been developed that allow the quantification of multiple cytokines and growth factors in tissues both at the level of protein [9] and mRNA using cDNA microarrays [10] and high-throughput complementary DNA sequencing (RNA-seq) [11] giving an increasingly more sensitive and global view of the psoriasis transcriptome (Fig. 2).…”

“…TNF-α is a somewhat enigmatic cytokine with respect to psoriasis pathogenesis; although it is produced by most activated T cells and APC, TNF-α alone does not evoke significant responses from cultured keratinocytes; however, in combination with IL-17A [102], IL-17C [65] and other cytokines it forms strong synergies, amplifying responses and thus is a significant element of the cytokine storm in psoriasis. Underlying the powerful synergism between TNF-α and IL-17A is the stabilization of IL-17A mRNA [103] by TNF-α, potentiating the effects of IL-17A, in addition to the ability of TNF-α to increase the expression of IL-17R by keratinocytes [9] and IL-17A to induce TNFR expression. Following the success of targeting TNF-α in arthritis, this approach was taken in psoriasis where several biologics are particularly effective (Fig.…”