Stat3 activation in epidermal keratinocytes induces Langerhans cell activation to form an essential circuit for psoriasis via IL-23 production

Abstract

Background: 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. Objectives: To elucidate whether LCs are functionally involved in the development of psoriasis using a mouse model. Methods: Two lines of transgenic mice were used and crossed. They included K5.Stat3C, the psoriasismodel 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. Results: 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. Conclusions: 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.

Review—Current Concepts in Inflammatory Skin Diseases Evolved by Transcriptome Analysis: In-Depth Analysis of Atopic Dermatitis and Psoriasis

“…However, the in vivo distinction of a rather DC-like state versus a macrophage-like state is nontrivial, and the role of Tip-DCs/macrophages is under debate [70,71]. Although a single prominent cell type might be responsible for a certain cytokine response in a specific disease state, the cytokine milieu is sustained by various contributors (e.g., Langerhans cells, inflammatory dendritic cells, and mast cells [72][73][74]).…”

Dendritic cells: The driver of psoriasis

“…Several studies exploiting the LC‐depleted mouse favor a contrasting outcome. Activation of the STAT3 pathway in keratinocytes and TLR in LC can induce LC to generate IL‐23, which is crucial in the pathogenesis of psoriasis . Mice with deletion of the p38α signal in LC produce much less IL‐23 and IL‐6, thereby reducing the psoriatic inflammation .…”

The role of Langerhans cells in epidermal homeostasis and pathogenesis of psoriasis

“…84 In addition, studies have shown that the activation of Stat3 in keratinocytes may affect the activation of LCs at least partly through IL-1 α stimulation, and their existence is related to the occurrence or aggravation of psoriasis, called the Koebner phenomenon, which is caused by IL-23. 85,86 This activation leads to the intraepidermal circuit of KC-LCs and the activation of the IL-23/IL-17 axis, which leads to the occurrence and development of psoriasis. Human β-defensin 3 (HBD3) is a small antimicrobial peptide that has a chemotactic effect on immune cells and plays a small role in promoting the development of psoriasis by inducing the increase of IL-23 produced by epidermal LCs.…”

“…In addition, studies have shown that the activation of Stat3 in keratinocytes may affect the activation of LCs at least partly through IL‐1 α stimulation, and their existence is related to the occurrence or aggravation of psoriasis, called the Koebner phenomenon, which is caused by IL‐23 85,86 . This activation leads to the intraepidermal circuit of KC‐LCs and the activation of the IL‐23/IL‐17 axis, which leads to the occurrence and development of psoriasis.…”