Letter to the Editor

Psoriasis-like skin lesions are dependent on IL-23 but develop in the absence of IL-22 in a model mouse

Alternaria longipes (A. longipes) is the main pathogen causing tobacco brown spot, one of the most severe diseases of tobacco. Numerous studies have indicated that miRNAs are widely involved in interactions between pathogens and host plants. To characterize the roles of miRNAs in A. longipes infection of Nicotiana benthamiana (N. benthamiana), specific infection methods to isolate infected and sampled regions of N. benthamiana leaves were used. The process of A. longipes infection of N. benthamiana leaves was characterized by determining a series of critical physiological indices. The results revealed that 3 days after infection by A. longipes was the critical stage of A. longipes infection of N. benthamiana leaves. miRNAs expressed in response to A. longipes infection were identified through sRNA high-throughput sequencing. A total of 175 novel miRNAs were identified in the N. benthamiana genome through 6 sRNA libraries. Of these, 37 miRNAs were differentially expressed between control and infected leaves. The abundance of 15 miRNAs, including nbe-miRN2031*, nbe-miR482b, and nbe-miR398, was found to be especially upregulated in leaves infected with A. longipes. These miRNAs mainly targeted resistance proteins of N. benthamiana. Further expression analysis of the miRNAs and their targets indicated that miRNAs substantially affected the expression of resistance genes during infection by A. longipes. Moreover, nbe-miR482b and nbe-miRN2031* transiently silenced via STTM technology decreased injury levels caused by A. longipes, suggesting that this fungus might regulate the immune response of host plants by regulating several key miRNAs. This study primarily clarified the potential roles of miRNAs during A. longipes infection and provided critical information for an in-depth understanding of the infection mechanism used by A. longipes on plants.

Psoriasis and periodontitis are immunologically mediated chronic inflammatory diseases. Epidemiologic evidence has linked both; however, the change of markers in gingival crevicular fluid has been poorly evaluated.

To evaluate the levels of IL-17A, IL-22, IL-23, S100A7, S100A8, and S100A9 in gingival crevicular fluid of psoriatic and healthy subjects with and without periodontitis and their relations to psoriasis severity.

Cross-sectional study. Sample comprised the following groups: healthy controls without periodontitis or with mild periodontitis (n = 21), healthy controls with moderate or severe periodontitis (n = 18), individuals with psoriasis without or mild periodontitis (n = 11), and individuals with psoriasis and moderate or severe periodontitis (n = 32). Levels of IL-17A, IL-22, IL-23, S100A8, and S100A9 were determined by multiplex assay and S100A7 was measured by ELISA.

No inter-group differences in the levels of IL-17A, IL-22, IL-23, and S100A7 were found. S100A8 levels were higher in psoriatic patients than controls (p < 0.05). S100A8 was positively correlated with psoriasis severity in the group with psoriasis (p < 0.05). S100A9 exceeded the detection limits.

This pilot study presents a small sample size.

The concentrations of S100A8 were highest in psoriatic patients regardless of periodontal health/status. S100A8 was associated with the severity of psoriasis. The concentrations of interleukins and S100A7 were similar in psoriatic patients with or without periodontitis vs. healthy controls.

Psoriasis is an inflammatory disease associated with aberrant crosstalk between the epidermis and immune system. However, the role of Langerhans cells (LCs) in psoriasis remains controversial.

To elucidate whether LCs are functionally involved in the development of psoriasis using a mouse model.

Two lines of transgenic mice were used and crossed. They included K5.Stat3C, the psoriasis-model mouse and langerin DTR knock-in (KI) mouse. We performed immunofluorescence staining for LCs in psoriatic lesion of human and model mice. Flow cytometric analyses were performed to compare between dendritic cells (DCs) and LCs in the epidermis and skin-draining lymph nodes (sDLNs). To assess cytokine/chemokine expression in the skin lesion or primary cultured keratinocytes, we performed RT-PCR, microarray analysis or intracellular staining on the flow cytometer.

LCs were activated in psoriatic lesion of patients with psoriasis and K5.Stat3C mice. Compared with non-transgenic mice, K5.Stat3C mice constitutively showed an increased number of LCs in the sDLNs before psoriasis-like lesion developed. Stat3C transgenic keratinocytes expressed an elevated level of IL-1α. Psoriasis-like lesion in K5.Stat3C mice were attenuated in the absence of LCs, indicating that LCs were essential to the development of psoriasis-like lesion. Furthermore, we also recognized that epidermal LCs in psoriatic lesion of not only K5.Stat3C mice but also psoriasis patients produced IL-23.

Our study suggests that Stat3 activation in keratinocytes may impact on LC activation in situ via IL-1α stimulation, at least in part, and that their presence may be essential for the pathogenesis of psoriasis through producing IL-23.

Targeting the IL-17 pathway represents a highly effective strategy for the treatment of psoriasis, using antibodies against IL-17A and IL-17 receptor, suggesting that Th17 cells essentially contribute to development of psoriasis. Th17 differentiation depends on the key transcription factor, RORγt.

To develop a novel RORγt antagonist which is effective on psoriasis via oral administration.

A chemical library was screened using cell-based high-throughput methods, luciferase reporter assay, competitive binding assay, and T cell differentiation assay. To evaluate in vivo effects of a novel RORγt antagonist, A213, we orally administrated it to two independent mouse models of psoriasis; IL-23-injection model and K5.Stat3C transgenic mouse.

Oral administration of A213 resulted in attenuation of skin inflammation in the both mouse models. At the same time, increased levels of IL-17A expression were significantly reduced in the skin lesions and skin-draining lymph nodes.

These results implicate a new therapeutic application of RORγt antagonist for the treatment of psoriasis.

Psoriasis is a systemic inflammatory disease in which IL-17 and IL-22 levels are markedly increased in the skin and blood. The prevalent concept, using skin cells that are isolated from psoriatic plaques and examined after cell expansion and in vitro stimulation, is that IL-17 and IL-22 production essentially results from T cells and the rare type 3 innate lymphoid cells.

We sought to examine the cellular source of IL-17A and IL-22 at the protein and transcriptional single-cell level immediately after ex vivo skin cell isolation from psoriatic plaques.

Skin biopsy specimens were collected from patients with psoriasis, as well as from patients with atopic dermatitis. Cell suspensions were prepared by combining mild enzymatic digestion and mechanical dissociation and analyzed for cytokine expression without prior in vitro culture and stimulation. Expression of IL-17 and IL-22 was quantified at the protein and mRNA single-cell level by using flow cytometry.

IL-22 is predominantly expressed by CD3⁻c-Kit⁺ cells relative to CD3⁺ T cells in lesional skin of patients with psoriasis and patients with atopic dermatitis. Strikingly, we identified c-Kit⁺FcεRI⁺ mast cells as major IL-22 producers. The proportion of mast cells that produce IL-22 ranges from 20% to 80% in patients with psoriasis or those with atopic dermatitis. Skin mast cells express IL-22 and IL-17 mRNA. Conversely, IL-17–producing T cells outnumber IL-17–producing mast cells, which also express IL-17 receptor.

Human skin mast cells are previously unrecognized IL-22 producers. We further established that skin mast cells express IL-17. Thus mast cells might play an important role in the physiopathology of chronic inflammatory skin disorders.

Atopic dermatitis (AD) and psoriasis are common inflammatory skin diseases. Although clinical pictures of these two diseases are quite different, they share some common pathological backgrounds such as barrier dysfunction and enhanced IL-22 expression. To explain the clinical differences of the diseases, it has been proposed that Th2/Th22-polarized immune status together with an attenuated Th17 axis may cause insufficient induction of antimicrobial peptides and more severe barrier dysfunction in AD. While skin barrier dysfunction is commonly seen in AD and psoriasis, a Th2-dominant cytokine milieu down-regulates immunity against infections, which are commonly seen in lesional skin of AD. In the era of biologics, increase in the understanding or new discoveries of molecules involved in the development of various diseases will instantly lead to a new therapeutic strategy. In this review, we give an overview of recent advances in AD and psoriasis, especially on genetic background, barrier function, and therapeutic targets.