IL‐17A synergistically enhances TLR3‐mediated IL‐36γ production by keratinocytes: A potential role in injury‐amplified psoriatic inflammation

Abstract

Skin injury can trigger formation of new lesions in psoriasis (Koebner phenomenon). The mechanisms through which injury exacerbates psoriasis are unclear. During wound repair, epidermal keratinocytes are activated and produce abundant IL‐36γ, further promoting the skin inflammation. IL‐17A is the cornerstone cytokine in the pathogenesis of psoriasis. We sought to investigate the effects of IL‐17A on injury‐induced keratinocyte activation and IL‐36γ production. Here, we demonstrated that dsRNA released from necrotic keratinocytes induced the expression of IL‐36γ. Silencing of TLR3 by siRNA decreased the IL‐36γ induction by necrotic keratinocyte supernatant. Co‐stimulation with dsRNA and IL‐17A synergistically increased the expression of IL‐36γ and other proinflammatory mediators (CCL20, CXCL8, DEFB4 and LCN2) in keratinocytes. The synergistic effects were not dependent on TLR3 upregulation, TNF receptor signalling and mRNA stabilization. Co‐stimulation with dsRNA and IL‐17A resulted in an accumulation of IκBζ. The synergistic upregulation of IL‐36γ and proinflammatory mediators were inhibited by IκBζ siRNA. Co‐stimulation with IL‐17A and poly(I:C) markedly activated the p38 MAPK and NF‐κB pathway, compared with poly(I:C). Blockade of p38 MAPK and NF‐κB suppressed dsRNA/IL‐17A–mediated IκBζ and IL‐36γ induction. These findings demonstrated that IL‐17A synergistically enhanced the dsRNA‐mediated IL‐36γ production through a p38 MAPK‐, NF‐κB–, and IκBζ‐dependent mechanism.

Koebner phenomenon leading to the formation of new psoriatic lesions: evidences and mechanisms

“…Keratinocytes may release IL-33, which activate the mast cells to release IL-6 [89]. Furthermore, TLR-3 released from the keratinocytes interacts with mast cell-derived IL-17 to induce the release of IL-36γ and other inflammatory mediators [21]. Mast cell-derived IL-17 activates p38MAPK and NF-kB STAT3 signaling pathway to induce Koebernization [21].…”

“…Furthermore, TLR-3 released from the keratinocytes interacts with mast cell-derived IL-17 to induce the release of IL-36γ and other inflammatory mediators [21]. Mast cell-derived IL-17 activates p38MAPK and NF-kB STAT3 signaling pathway to induce Koebernization [21]. Considering these mechanisms, it may be proposed that the pharmacological modulation of mast cells, tryptase, IL6, IL-8, IL-17, IL-33, IL-36γ, p38MAPK, and NF-kB may serve to inhibit the induction and/or progression of new psoriatic lesions following skin injury.…”

“…IL-17A and TLR3-mediated synergistic up-regulation of IL-36γ and other pro-inflammatory mediators were inhibited in the presence of siRNA of IκBζ and blockers of p38 mitogen-activated protein kinase (MAPK) and NF-κB. It suggests that IL-17A-mediated inflammatory actions in Koebner phenomenon are dependent on the activation of p38 MAPK and NF-κB [21]. Indeed, NF-kB has been reported as a key transcriptional factor of psoriasis [81,82] and different pharmacological agents including quercetin and BAY 11-7082 are shown to inhibit the development of psoriatic lesion by inhibiting the activation of this transcriptional factor [83].…”

“…Indeed, a number of agents/triggers have been reported to induce the development of new psoriatic lesions in healthy skin areas and these include, tattooing skin, radiations, skin incision, viral infections, and striae etc [17][18][19]. The different mechanisms that may possibly contribute in inducing the development of new psoriatic lesions as Koebernization include the involvement of mast cell-derived inflammatory mediators [20][21][22], nerve growth factor (NGF) and its receptor system [23], vascular endothelial growth factor (VEGF) [24], α 2 β1 integrins [25], S100A7 (psoriasin) and S100A15 (koebnerisin) [26], increase in the ratio of CD4 + /CD8 + T cells [5], down-regulation of polycystins [27], down-regulation of atypical chemokine receptor 2 (ACKR2) [28], decreased expression of N-methyl-d-aspartate (NMDA) receptor (NMDAR) on the keratinocytes [29] and increase in chemokines [30]. The present review discusses the role of Koebner phenomenon in the development of new psoriatic lesions at the healthy body parts in response to an injury with possible mechanisms.…”

The Immune Functions of Keratinocytes in Skin Wound Healing

“…Of note, TLR3 activation in the skin epithelium is essential for the normal immune response after injury [19]. TLR3 recognizes viral double-stranded RNA (dsRNA), as well as dsRNA derived from damaged cells, which results in the keratinocyte expression of cytokines, including IFN-β, interleukins 8, 18, 36γ (IL-8, IL-18, IL-36γ) and tumor necrosis factor alpha (TNF-α) [16][17][18], as well as chemokines, such as C-C motif chemokine ligands 20 and 27 (CCL20 and CCL27) [9]. Exposure to dsRNA further upregulates the expression of dsRNA-sensing receptors, such as TLR3, but also single-stranded RNA (ssRNA) sensing receptor TLR7, which is barely expressed in keratinocytes under homeostatic conditions [20,21].…”