IMQ-induced Psoriasis Research Articles

IL-6 Signaling in Myelomonocytic Cells Is Not Crucial for the Development of IMQ-Induced Psoriasis.

Psoriasis is an autoimmune skin disease that is associated with aberrant activity of immune cells and keratinocytes. In mice, topical application of TLR7/8 agonist IMQ leads to a skin disorder resembling human psoriasis. Recently, it was shown that the IL-23/ IL-17 axis plays a deciding role in the pathogenesis of human psoriasis, as well as in the mouse model of IMQ-induced psoriasis-like skin disease. A consequence of IL-17A production in the skin includes increased expression and production of IL-6, resulting in the recruitment of neutrophils and other myelomonocytic cells to the site of inflammation. To further investigate and characterize the exact role of IL-6 signaling in myelomonocytic cells during experimental psoriasis, we generated mice lacking the IL-6 receptor alpha specifically in myelomonocytic cells (IL-6RαΔmyel). Surprisingly, disease susceptibility of these mice was not affected in this model. Our study shows that classical IL-6 signaling in myelomonocytic cells does not play an essential role for disease development of IMQ-induced psoriasis-like skin disease.

Paeoniflorin inhibits imiquimod-induced psoriasis in mice by regulating Th17 cell response and cytokine secretion

Paeoniflorin (PF) is the main active ingredients of radix paeoniae rubra and radix paeoniae alba, which are used widely in Traditional Chinese Medicine. This study aimed to assess the capacity of PF to inhibit imiquimod (IMQ)-induced psoriasis. Mice treated with IMQ were divided into four groups and administered 240mg/kg/day or 120mg/kg/day of PF, 1mg/kg/day of methotrexate (MTX), or normal saline intragastrically. Weight-matched mice treated with vaseline were used as controls. Morphology, structural features, keratinocyte proliferation and differentiation, inflammatory cell infiltration, levels of Th1/Th2/Th17/Treg cytokine mRNA, and phosphorylation of Th17 differentiation-related proteins were assessed. Mouse spleen cells were incubated under Th17 polarizing conditions, then with PF (2, 20, and 200μg/ml) and cell viability, Th17 differentiation, and Th17 cytokines and the orphan nuclear receptor (RORγt) mRNA levels were assessed. PF alleviated IMQ-induced keratinocyte proliferation and inflammatory cell infiltration, and reduced mRNA levels of Th17 cytokines at day 4 and phosphorylation of Th17 differentiation-related proteins. However, 2, 20, or 200μg/ml PF did not affect spleen cell viability, and 2 and 20μg/ml PF reduced IL-17 secretion under Th17 polarizing conditions. Finally, 2 and 20μg/ml PF inhibited mRNA expression of Th17 cytokines and phosphorylation of Stat3 in spleen cells under Th17 polarizing conditions. These results suggest that PF inhibits IMQ-induced psoriasis by regulating Th17 cell response and cytokine secretion via phosphorylation of Stat3.

IL-22/STAT3-Induced Increases in SLURP1 Expression within Psoriatic Lesions Exerts Antimicrobial Effects against Staphylococcus aureus.

Background SLURP1 is the causal gene for Mal de Meleda (MDM), an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma and transgressive keratosis. Moreover, although SLURP1 likely serves as an important proliferation/differentiation factor in keratinocytes, the possible relation between SLURP1 and other skin diseases, such as psoriasis and atopic dermatitis, has not been studied, and the pathophysiological control of SLURP1 expression in keratinocytes is largely unknown.ObjectivesOur aim was to examine the involvement of SLURP1 in the pathophysiology of psoriasis using an imiquimod (IMQ)-induced psoriasis model mice and normal human epidermal keratinocytes (NHEKs).ResultsSLURP1 expression was up-regulated in the skin of IMQ-induced psoriasis model mice. In NHEKs stimulated with the inflammatory cytokines IL-17, IL-22 and TNF-α, which are reportedly expressed in psoriatic lesions, SLURP1 mRNA expression was significantly up-regulated by IL-22 but not the other two cytokines. The stimulatory effect of IL-22 was completely suppressed in NHEKs treated with a STAT3 inhibitor or transfected with siRNA targeting STAT3. Because IL-22 induces production of antimicrobial proteins in epithelial cells, the antibacterial activity of SLURP1 was assessed against Staphylococcus aureus (S. aureus), which is known to be associated with disease severity in psoriasis. SLURP1 significantly suppressed the growth of S. aureus.ConclusionsThese results indicate SLURP1 participates in pathophysiology of psoriasis by regulating keratinocyte proliferation and differentiation, and by suppressing the growth of S. aureus.

109 : Critical cell-type specific functions of the Il-17 receptor signaling adaptor CIKS/ACT1 in imiquimod-induced psoriasis

Psoriasis is a relapsing skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory immune cells. The IL-23/IL-17 cytokines axis is thought to play an important role in the pathogenesis of psoriasis. The TLR7/8 ligand Imiquimod (IMQ) can induce/exacerbate psoriasis in patients and it induces a psoriasis-like condition in mice. In addition to IL-17A and IL-17F, which are produced by dermal γδ T, Th17 and innate lymphoid cells, the keratinocyte-derived IL-17C has also recently been implicated in IMQ-induced psoriasis. To determine by what mechanisms IL-17 cytokines critically contribute to psoriasis, we investigated a mouse model in which signaling by all IL-17 cytokines is abrogated due to the loss of the obligate adaptor protein CIKS/Act1. Importantly, the gene for this adaptor protein has also been identified as a strong susceptibility locus in psoriasis. Here we show that IMQ applications induced many of the typical phenotypes of human psoriasis in wild-type mice, but largely failed to do so in CIKS-deficient mice. In addition to promoting the influx of inflammatory cells, IL-17 signaling via CIKS contributed to increased proliferation of keratinocytes and inhibited their terminal differentiation. Mice lacking CIKS in keratinocytes only were protected from some, but not all of the pathologic phenotypes associated with psoriasis in this model. Keratinocytes are thus an important, though not the only cell type in which CIKS contributes to disease. These data demonstrate that CIKS is essential for IMQ-induced psoriasis by mediating the signaling of IL-17 cytokines in several distinct cell types. Thus our findings identify CIKS as a promising target for therapeutic intervention in this disease.

The adaptor protein CIKS/Act1 is essential for imiquimod-induced psoriasis. (P6269)

Abstract Psoriasis is a skin disease characterized by abnormal keratinocyte (KC) proliferation and differentiation and by an influx of inflammatory immune cells. The IL-23/IL-17 axis is thought to play an important role in the pathogenesis of psoriasis. Imiquimod (IMQ) can induce/exacerbate psoriasis in patients and it induces a psoriasis-like condition in mice. In addition to IL-17A/F, IL-17C has also recently been implicated in IMQ-induced psoriasis. To determine by what mechanisms IL-17 cytokines critically contribute to psoriasis, we investigated a mouse model in which signaling by all IL-17 cytokines is abrogated due to the loss of the obligate adaptor protein CIKS/Act1. Importantly, the gene for CIKS has also been identified as a strong susceptibility locus in psoriasis. Here we show that IMQ induced many of the typical phenotypes of human psoriasis in wild-type mice, but largely failed to do so in CIKS-deficient mice. In addition to promoting the influx of inflammatory cells, IL-17 signaling via CIKS contributed to increased proliferation of KCs and inhibited their terminal differentiation. Mice lacking CIKS in KCs only were protected from some, but not all of the pathologic phenotypes associated with psoriasis in this model. These data demonstrate that CIKS is essential for IMQ-induced psoriasis by mediating the signaling of IL-17 cytokines in several distinct cell types. Thus our findings identify CIKS as a promising target for therapeutic intervention in this disease.

The adaptor protein CIKS/Act1 is essential for imiquimod-induced psoriasis. (171.25)

Abstract Psoriasis is a relapsing skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory immune cells. The IL-23/IL-17 cytokines axis is thought to play an important role in the pathogenesis of psoriasis. The TLR7/8 ligand Imiquimod (IMQ) can induce/exacerbate psoriasis in patients and it induces a psoriasis-like condition in mice. In addition to IL-17A and IL-17F, which are produced primarily by Th17 and innate T cells, IL-17C has very recently been implicated in IMQ-induced psoriasis as well. To determine by what mechanisms IL-17 cytokines critically contribute to IMQ-induced psoriasis, we have begun to investigate a mouse model in which signaling by all IL-17 cytokines is abrogated due to the loss of the obligate adaptor protein CIKS/Act1. Importantly, the gene for this adaptor protein has also recently been identified as a strong susceptibility locus in psoriasis. Here we show that IMQ applications induced many markers of psoriasis in wild-type mice, but failed to do so in CIKS-deficient mice. These data demonstrate that signaling by IL-17 cytokines via the adaptor protein CIKS is essential for IMQ-induced psoriasis and thus the CIKS pathway may provide targets for therapeutic intervention in psoriasis. We will report on the progress in understanding the functions of IL-17 cytokines in development of psoriasis.