Pathophysiology of psoriasis: A review Yamanaka, Keiichi; Yamamoto, Osamu; Honda, Tetsuya
Journal of dermatology,
June 2021, Letnik:
48, Številka:
6
Journal Article
Recenzirano
Psoriasis is a complex chronic inflammatory skin disease caused by the dynamic interplay between multiple genetic risk foci, environmental risk factors, and excessive immunological abnormalities. ...Psoriasis affects approximately 2% of the population worldwide, and dramatic advances have been achieved in the understanding and treatment options for psoriasis. Recent progress in biological therapies has revealed the fundamental roles of tumor necrosis factor‐α, interleukin (IL)‐23p19, and the IL‐17A axis together with skin‐resident immune cells and major signal transduction pathways in the pathogenesis of psoriasis. In addition to IL‐17‐producing T helper17 cells, innate lymphoid cell (ILC)3 induces psoriasis rashes directly without T‐cell/antigen interaction in response to the released antimicrobial peptides from activated keratinocytes and inflammatory cytokines. ILC3 typically expresses retinoic acid receptor‐related orphan receptor gamma t in the nucleus, matures in the presence of IL‐7 and IL‐23, and produces IL‐17 and IL‐22. The number of ILC3s is increased in the blood, psoriasis rash, and even in nonrash areas of psoriatic skin. Psoriasis is significantly associated with cardiovascular disease, metabolic syndrome, and inflammatory disorders, particularly the severe type. The similarity of enterobacteria in the psoriasis gut to that in diabetic patients may be related to its pathogenesis. In the current review, we focus on the pathophysiology of psoriasis in the accelerated immunological inflammatory loop, danger signal from keratinocytes, and cytokines, particularly IL‐17 and IL‐23p19. In addition, pathophysiological speculation with regard to morphology has been supplemented. Finally, the differences and similarities between psoriasis and atopic dermatitis are discussed.
Lipid mediators, such as prostanoids and leukotrienes (LTs), exert a range of actions through their own receptors on cell surfaces in various pathophysiological conditions. It has been reported that ...the production of prostanoids and LTs is significantly elevated in the skin lesions of some chronic inflammatory skin diseases, such as atopic dermatitis (AD) and psoriasis, showing the possible involvement of these lipid mediators in the development of those diseases. Although the actual significance of these lipid mediators in humans is still unclear, the findings from studies in mice suggest diverse roles of the lipid mediators in the progression or regulation of these diseases. For example, in a mouse AD model, prostaglandin D2 inhibits the induction of Th2 cells through DP receptor on Langerhans cells, while it promotes infiltration of Th2 cells through chemoattractant receptor-homologous molecule expressed on Th2 cells. In a psoriasis model, thromboxane A2-TP signaling promotes psoriatic dermatitis by facilitating IL-17 production from γδ T cells. In this short review, we summarize the current findings on the roles of prostanoids and LTs in AD and psoriasis as revealed by studies in mice, and discuss the potential of these lipid mediators as therapeutic targets in humans.
Abstract
Atopic dermatitis (AD) is a common T-cell-mediated inflammatory disease of the skin. Signatures of AD are characterized by an impaired skin barrier, aberrant Th2-type cytokine production and ...intensive pruritus. Transcriptomic analysis, however, has revealed a heterogeneous pathogenesis and the co-existence of multiple cytokine axes of Th17, Th22 and Th1 types, especially in intrinsic (a subtype of AD without skin barrier impairment), pediatric and Asian types of AD. Furthermore, the therapeutic effect of anti-IL-4 receptor α against AD was not as high as that of IL-17 blockage against psoriasis, which implies a modification of the disease spectrum by non-Th2-type cytokine axes in AD. These lines of evidence indicate a need for personalized or precision medicine appropriate for each subtype of AD.
Allergic contact dermatitis (ACD) is one of the most common skin diseases, consisting of sensitization and elicitation phases. With the advancement of technology and the discovery of new types of ...immune cells, our knowledge of the immunological mechanisms of contact hypersensitivity (CHS) as a murine model of ACD has expanded significantly in the past decade. For example, by introducing regulatory T cells, CD4+ T-helper 17 cells, and Langerin-positive dermal dendritic cells, the initiation and termination mechanism of CHS has been revealed. In addition, the role of mast cells in CHS, long a matter of debate, has become apparent by developing conditional mast cell–deficient mice. Moreover, the role of the innate immunity system, such as that of Toll-like receptor signaling, has made a breakthrough in this field. In this review, we will integrate the recent advancement of immunological mechanisms of both the sensitization and elicitation phases of CHS into the classic view, and we will discuss updated mechanisms on its development and future directions.
For the induction of adequate cutaneous immune responses, the antigen presentation and recognition that occur in both the skin and skin-draining lymph nodes are essential. In each process of ...cutaneous immune responses, several distinct subsets of immune cells, including dendritic cells and T cells, are involved, and they elicit their respective functions in a harmonious manner. For example, in the elicitation phase of cutaneous acquired immunity, immune cells form a specific lymphoid structure named inducible skin-associated lymphoid tissue (iSALT) to facilitate efficient antigen presentation in situ. In this short review, we will overview the mechanisms of how antigens are presented and how cutaneous adaptive immune responses are conducted in the skin, especially focusing on contact hypersensitivity, a prototypic adaptive immune response in the skin.
Dietary lipids are fundamental nutrients for human health. They are typically composed of various long-chain fatty acids which include saturated fatty acids (SFAs) and unsaturated fatty acids (UFAs). ...UFAs are further classified into several groups, such as omega-3 polyunsaturated fatty acids (PUFAs) and omega-6 PUFAs, depending on their chemical structure. Epidemiological studies have suggested the involvement of dietary lipids in the progression or regulation of psoriasis, a common chronic inflammatory skin disease induced via the IL-23/IL-17 axis. Although the underlying mechanisms by which dietary lipids regulate psoriasis have remained unclear, with the advancement of experimental techniques and the development of psoriasis mouse models, various possible mechanisms have been proposed. For example, SFAs may facilitate psoriatic dermatitis by causing activation of the inflammasome in keratinocytes and macrophages or by inducing IL-17-producing cells, such as Th17 and IL-17-producing γδ T cells in the skin, while omega-3 PUFAs may play inhibitory roles by suppressing Th17 differentiation. In this review, we summarize current data on the roles of dietary lipids in the development of psoriasis as revealed by mouse studies, and we discuss potential therapeutic strategies for psoriasis from the perspective of dietary lipids.
Skin is a frontline organ that is continuously exposed to external stimuli, including pathogens. Various immune cells reside in the skin under physiological conditions and protect the body from the ...entry of pathogens/antigens by interacting with each other and orchestrating diverse cutaneous immune responses. To avoid unnecessary inflammation and tissue damage during the elimination of external pathogens and antigens, skin possesses regulatory systems that fine-tune these immune reactions. Mast cells (MCs) are one of the skin-resident immune cell populations that play both effector and regulatory functions in the cutaneous immune response. So far, the interleukin-10-mediated mechanisms have mostly been investigated as the regulatory mechanisms of MCs. Recent studies have elucidated other regulatory mechanisms of MCs, such as the maintenance of regulatory T/B cells and the programmed cell death protein-1/programmed cell death-ligand 1-mediated inhibitory pathway. These regulatory pathways of MCs have been suggested to play important roles in limiting the excessive inflammation in inflammatory skin diseases, such as contact and atopic dermatitis. The regulatory functions of MCs may also be involved in the escape mechanisms of antitumor responses in skin cancers, such as melanoma. Understanding and controlling the regulatory functions of skin MCs may lead to novel therapeutic strategies for inflammatory skin diseases and skin cancers.
Alopecia areata has basically been understood as a type 1 inflammatory disease. Activated NKG2D+CD8+ cells produce the Th1 cytokine interferon‐γ, which leads to the disruption of immune tolerance of ...hair follicles and the exposure of self‐antigens. This results in dense inflammatory cell infiltration and apoptosis around hair follicles, inducing hair loss. A well‐known complication of alopecia areata is atopic dermatitis, a typical type 2 inflammatory disease. Hair scientists have shied away from confronting and understanding how alopecia areata, a type 1 inflammatory disease, and atopic dermatitis, a type 2 inflammatory disease, can occur together. This review summarizes the research on the cytokine balance in alopecia areata and then focuses on the classification of the cytokine balance in alopecia areata, including the classification of atopic dermatitis into extrinsic and intrinsic types. Dupilumab reportedly showed dual efficacy in a patient with concomitant atopic dermatitis and alopecia areata, supporting our own experience. Elevated Th2 cytokine levels have also been reported in patients with alopecia areata, with increased serum IL‐4, IL‐5, IL‐6 levels, high IgE levels and elevated eosinophil levels. Because local immunotherapy is a treatment that induces Th2‐type inflammation, it may worsen the condition of alopecia areata patients with extrinsic atopic dermatitis. It is desirable to select appropriate treatments with consideration of the cytokine balance.
Mast cells (MCs) are immune cells residing in tissues and playing indispensable roles in maintaining homeostasis and inflammatory states. Skin lesions associated with atopic dermatitis (AD) and type ...2 skin inflammation display an increment in MCs, which have both pro‐ and anti‐inflammatory effects. The direct and indirect activations of skin MCs by environmental factors such as Staphylococcus aureus can instigate type 2 skin inflammation in AD with poorly understood mechanisms. Furthermore, both IgE‐dependent and ‐independent degranulation of MCs contribute to pruritus in AD. Conversely, MCs suppress type 2 skin inflammation by promoting Treg expansion through IL‐2 secretion in the spleen. Moreover, skin MCs can upregulate gene expression involved in skin barrier function, thus mitigating AD‐like inflammation. These functional variances of MCs in AD could stem from differences in experimental systems, their localization, and origins. In this review, we will focus on how MCs are maintained in the skin under homeostatic and inflammatory conditions, and how they are involved in the pathogenesis of type 2 skin inflammation.
Mast cells exhibit pro‐ and anti‐inflammatory effects in atopic dermatitis, type 2 skin inflammation. These functional differences may arise from different experimental systems, their localization, and their origins.
Summary
Prostanoids and leukotrienes (LTs) are representative of ω6 fatty acid‐derived metabolites that exert their actions through specific receptors on the cell surface. These lipid mediators, ...being unstable in vivo, act locally at their production sites; thus, their physiological functions remain unclear. However, recent pharmacological and genetic approaches using experimental murine models have provided significant insights into the roles of these lipid mediators in various pathophysiological conditions, including cutaneous inflammatory diseases. These lipid mediators act not only through signaling by themselves but also by potentiating the signaling of other chemical mediators, such as cytokines and chemokines. For instance, prostaglandin E2‐EP4 and LTB4‐BLT1 signaling on cutaneous dendritic cells substantially facilitate their chemokine‐induced migration ability into the skin and play critical roles in the priming and/or activation of antigen‐specific effector T cells in the skin. In addition to these ω6 fatty acid‐derived metabolites, various ω3 fatty acid‐derived metabolites regulate skin immune cell functions, and some exert potent anti‐inflammatory functions. Lipid mediators act as modulators of cutaneous immune responses, and manipulating the signaling from lipid mediators has the potential as a novel therapeutic approach for human skin diseases.
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