Recent research into the pathophysiology and treatment of atopic dermatitis (AD) has shown notable progress. An increasing number of aspects of the immune system are being implicated in AD, including the epithelial barrier, TH2 cytokines, and mast cells. Major advances in therapeutics were made in biologic cytokine and receptor antagonists and among Janus kinase inhibitors. We focus on these areas and address new insights into AD epidemiology, biomarkers, endotypes, prevention, and comorbidities. Going forward, we expect future mechanistic insights and therapeutic advances to broaden physicians ability to diagnose and manage AD patients, and perhaps to find a cure for this chronic condition.

Erythrodermic psoriasis (EP) is an extreme and often refractory variant of psoriasis with high morbidity and increased mortality, and is frequently classified as a dermatological emergency. The pathophysiology of EP is largely unknown but is thought to differ from that of plaque psoriasis. Treatment of EP is challenging, and usually based on clinical experience and patient co-morbidities, due to its low incidence and limited clinical evidence. Conventional treatments, such as topical glucocorticoid therapy, cyclosporin, acitretin, and methotrexate have some but limited efficacy in EP, and treatment discontinuation may result in flares. Newer biological drugs, including anti-TNF, anti-IL-17, and anti-IL-12/23 agents, have shown promise in therapeutic management of EP, but most of the available evidence is currently based on small case series and reports. Few studies have compared available treatment options for EP, and further clinical studies are necessary to provide clinical data and optimal treatment guidelines for EP patients. Here, we provide a comprehensive review of the background of EP, assess the available clinical data on the efficacy of targeted therapies, and aim to provide a foundation for clinical decision making for this rare form of psoriasis.

As the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time of the patient or the tissue of focus is essential in circadian medicine and research. Here we present tauFisher, a computational pipeline that accurately predicts circadian time from a single transcriptomic sample by finding correlations between rhythmic genes within the sample. We demonstrate tauFisher's performance in adding timestamps to both bulk and single-cell transcriptomic samples collected from multiple tissue types and experimental settings. Application of tauFisher at a cell-type level in a single-cell RNAseq dataset collected from mouse dermal skin implies that greater circadian phase heterogeneity may explain the dampened rhythm of collective core clock gene expression in dermal immune cells compared to dermal fibroblasts. Given its robustness and generalizability across assay platforms, experimental setups, and tissue types, as well as its potential application in single-cell RNAseq data analysis, tauFisher is a promising tool that facilitates circadian medicine and research.

Psoriasis is a chronic inflammatory condition characterized by systemic immune dysregulation. Over the past several years, advances in genetics, microbiology, immunology, and mouse models have revealed the complex interplay between the heritable and microenvironmental factors that drive the development of psoriatic inflammation. In the first of this two-part review series, the authors will discuss the newest insights into the pathogenesis of psoriatic disease and highlight how the evolution of these scientific fields has paved the way for a more personalized approach to psoriatic disease treatment.

Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations. Plaque psoriasis, which is the most common manifestation of psoriasis, is located on one end of the spectrum, dominated by adaptive immune responses, whereas the rarer pustular psoriasis lies on the opposite end, dominated by innate and autoinflammatory immune responses. In recent years, genetic studies have identified six genetic variants that predispose to pustular psoriasis, and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis. In this review, we discuss the presentation and clinical subtypes of pustular psoriasis, contribution of genetic predisposing variants, critical role of the IL-36 family of cytokines in disease pathophysiology, and treatment perspectives for pustular psoriasis. We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.

Transcription factor binding, chromatin modifications and large scale chromatin re-organization underlie progressive, irreversible cell lineage commitments and differentiation. We know little, however, about chromatin changes as cells enter transient, reversible states such as migration. Here we demonstrate that when human progenitor keratinocytes either differentiate or migrate they form complements of typical enhancers and super-enhancers that are unique for each state. Unique super-enhancers for each cellular state link to gene expression that confers functions associated with the respective cell state. These super-enhancers are also enriched for skin disease sequence variants. GRHL3, a transcription factor that promotes both differentiation and migration, binds preferentially to super-enhancers in differentiating keratinocytes, while during migration, it binds preferentially to promoters along with REST, repressing the expression of migration inhibitors. Key epidermal differentiation transcription factor genes, including GRHL3, are located within super-enhancers, and many of these transcription factors in turn bind to and regulate super-enhancers. Furthermore, GRHL3 represses the formation of a number of progenitor and non-keratinocyte super-enhancers in differentiating keratinocytes. Hence, chromatin relocates GRHL3 binding and enhancers to regulate both the irreversible commitment of progenitor keratinocytes to differentiation and their reversible transition to migration.

The skin serves as the primary interface between our body and the external environment and acts as a barrier against entry of physical agents, chemicals, and microbes. Keratinocytes make up the main cellular constitute of the outermost layer of the skin, contributing to the formation of the epidermis, and they are crucial for maintaining the integrity of this barrier. Beyond serving as a physical barrier component, keratinocytes actively participate in maintaining tissue homeostasis, shaping, amplifying, and regulating immune responses in skin. Keratinocytes act as sentinels, continuously monitoring changes in the environment, and, through microbial sensing, stretch, or other physical stimuli, can initiate a broad range of inflammatory responses via secretion of various cytokines, chemokines, and growth factors. This diverse function of keratinocytes contributes to the highly variable clinical manifestation of skin immune responses. In this Review, we highlight the highly diverse functions of epidermal keratinocytes and their contribution to various immune-mediated skin diseases.

The circadian clock coordinates a variety of immune responses with signals from the external environment to promote survival. We investigated the potential reciprocal relationship between the circadian clock and skin inflammation. We treated mice topically with the Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ) to activate IFN-sensitive gene (ISG) pathways and induce psoriasiform inflammation. IMQ transiently altered core clock gene expression, an effect mirrored in human patient psoriatic lesions. In mouse skin 1 d after IMQ treatment, ISGs, including the key ISG transcription factor IFN regulatory factor 7 (Irf7), were more highly induced after treatment during the day than the night. Nuclear localization of phosphorylated-IRF7 was most prominently time-of-day dependent in epidermal leukocytes, suggesting that these cell types play an important role in the diurnal ISG response to IMQ. Mice lacking Bmal1 systemically had exacerbated and arrhythmic ISG/Irf7 expression after IMQ. Furthermore, daytime-restricted feeding, which affects the phase of the skin circadian clock, reverses the diurnal rhythm of IMQ-induced ISG expression in the skin. These results suggest a role for the circadian clock, driven by BMAL1, as a negative regulator of the ISG response, and highlight the finding that feeding time can modulate the skin immune response. Since the IFN response is essential for the antiviral and antitumor effects of TLR activation, these findings are consistent with the time-of-day-dependent variability in the ability to fight microbial pathogens and tumor initiation and offer support for the use of chronotherapy for their treatment.