Pathogenesis and Treatment of Atopic Dermatitis: Lessons From China

Abstract

Atopic dermatitis (AD) is a complex and heterogeneous skin disease characterised by Th2-dominant inflammation with differential contribution of Th22-, Th17- or Th1-type cells and molecules, which results from interactions among genetic susceptibility, environmental factors, barrier function, skin microbiome and immune responses. AD has been attracting increasing attention from both the public and academic society in China during the past 10 years. More and more dermatologists are pursuing in research on AD, covering almost all aspects of AD which span from genetics, clinical features and endotypes, to pathogenesis and innovative treatment. Chinese patients with AD share the common features with the patients from western countries on the one hand and, on the other hand, present with unique clinical and molecular phenotypes, which helps to enrich the understanding on AD and indicates special consideration for therapy.

Ethnic heterogeneity of AD has long been an interesting topic in this field. It has been reported that Chinese patients with AD are characterised with blended AD–psoriasis phenotype and endotype [1]. Chronic lichenification is commonly seen in Chinese patients with AD, accompanied by epidermal hyperplasia and an increased infiltration of Th17-related molecules in the lesional skin [1]. Recently, the application of bulk RNA-sequencing technique has revealed distinct inflammation patterns in the skin lesions of Chinese patients with AD across different ages. There is a notable upregulation in Th2 and Th17 inflammation in children, a significant increase in Th2 and Th22 inflammation in adults, and a marked decline of Th2 and Th22 inflammation in the elderly. In elderly patients with AD, genes related to skin barrier function, natural killer cells, macrophages, senescence-associated secretory phenotype and fibroblasts within the skin lesions have also been found. These findings collectively underscored the heterogeneity of AD and emphasised the urgent need for detailed researches to inform future precise therapies [2].

Apart from the endotype, dermatologists in China frequently encounter patients with AD with ‘atypical’ manifestations, many of them present with mild, localised or special forms of skin lesions. Unlike the referral system in western countries, where patients with skin conditions typically visit dermatologist following a referral from a primary care physician, in China, patients usually consult dermatologists directly. This practice allows Chinese dermatologists to see patients with AD with all kinds of manifestations, posing a challenge on diagnosis of AD. Researchers in China have dedicated great efforts to developing diagnostic criteria for AD (Table 1) [3], which have greatly advanced the understanding and awareness of AD in China. Elderly AD, a relatively new subtype distinct from infantile, childhood and adult AD, has attracted increasing attention. Wang et al. have delineated the clinical features and serum biomarkers of elderly AD in China [4]. The skin lesions in elderly AD are diverse, and more widely distributed compared with the flexure predilection seen in childhood AD. There is an increased proportion of intrinsic AD among the elderly [4]. The serum biomarker of elderly AD is featured with elevated proportion of Th17- and Th22-type cytokines/chemokines, aligning with previous findings in Caucasian AD populations [4]. However, the underlying molecular mechanisms associated with atypical AD (morphology, lesion location and age) remain unclear and need to be elucidated in the future.

Genetics analysis have also shown the common and unique features of Chinese patients with AD. Previous studies have reported that susceptible genes of AD are mainly related with barrier function or type 2 immune responses. Xiao et al. performed the first genome-wide association study of AD in the Chinese Han population and identified previously unknown susceptibility loci at 5q22.1 (TMEM232 and SLC25A46) and 20q13.33 (TNFRSF6B and ZGPAT), while also replicated the previously reported locus at 1q21.3 (FLG). Subsequent studies have demonstrated that TMEM232 exacerbates inflammation responses through activating the pathway of NF-κB and STAT3, which are regulated by IL4/ STAT6 axis in AD [5]. These findings provide possible target for future treatment of AD. Epigenetic mechanisms are also involved in the pathogenesis of AD. Liang et al. have shown that monocytes from PBMCs of patients with AD demonstrate a global hypomethylation, with locus-specific hypomethylation at FCER1G promoter, which is inversely correlated with its expression. They further elucidated that TSLP mediated upregulation of FcRg-related receptors on APCs through activation of pSTAT5, recruiting TET2 to induce FCER1G demethylation [6]. Further utilisation of the rich genetic resources of Chinese patients with AD would provide more information for AD pathogenesis and therapeutic targets.

The prevalence of AD in China has been increasing significantly during the past two decades, which indicates that environmental factors, such as air pollution, microbial exposure and life style, might play a role in the pathogenesis of AD. Microbial exposure is one of the most important factors affecting the onset of AD, which has long been encapsulated within the hygiene hypothesis. Recently, Liu et al. have revealed a link between hygiene levels in the residential environments and the occurrence of AD, as well as serum IgE levels. They also found that extrinsic AD and intrinsic AD exhibited different enrichment patterns for specific microbes and differential associations of functional pathways [7]. The Chinese population could serve as a good model for investigation of the effects of environment on AD, given the dramatic changes in living conditions due to rapid economic development.

In addition to environmental microbes, skin microbiota also plays an important role in AD. Early studies have shown that both lesional and non-lesional skin of patients with AD exhibit reduced Shannon diversity and increased abundance of S. aureus. Recently, Yu et al. found that the level of indole-3-aldehyde (IAId), a metabolite of tryptophan, was significantly decreased on the skin surface of patients with AD. IAId inhibited the production of TSLP by keratinocytes through binding to aryl hydrocarbon Receptor (AhR), thereby attenuating the skin inflammation in a MC903-induced AD mouse model [8]. This is the first study exploring the skin microbial metabolism and suggests that modulation of the metabolism of skin microbiota or utilisation of microbial metabolites may be helpful for the treatment of AD. Next, they explored the microbial metabolism of sebum and the role of Cutibacterium acnes (C. acnes, previously Propionibacterium acnes) in AD, as it has been reported that the number and size of sebaceous gland of patients with AD are reduced in patients with AD. The result showed that propionate was the most abundant SCFA on healthy skin, which was decreased significantly in patients with AD. Notably, propionate was found to inhibit the production of IL-33 by keratinocytes through binding to AhR and/or influencing histone deacetylase 2/3 (Figure 1). They also collected 1234 C. acnes strains from the skin of patients with AD, patients with acne and healthy individuals. Integrated analysis of whole genome sequencing, transcriptome and metabolome data revealed individual and niche heterogeneity among C. acnes [9]. As C. acnes is the most abundant bacterium in the human skin microbiome since adolescence, participating in both skin homeostasis and diseases, it potentially be developed as a topical probiotics for the treatment of AD. Sebum is crucial for regulation of the skin microbiota, not only modulating the abundance and composition of skin microbes but also impacting skin homeostasis through microbial metabolites (Figure 1).

In summary, Chinese patients with AD share the common features of AD compared with western countries and also demonstrate unique manifestations. The dramatic changes in life style and environment have profound impacts on the development and severity of AD. Advances in research on pathogenesis and treatment of AD in China have contributed a lot to recognition of the disease, which would be instrumental in developing new strategies for better management of AD.

X.Y. and W.L. designed the study and wrote the manuscript.

The authors declare no conflicts of interest.