Background

Atopic dermatitis (AD), also known as atopic eczema, is a common and long-lasting skin condition that primarily manifests as severe itching and inflammation.1,2 Epidemiologic studies have shown that AD affects a significant proportion of the world's population, with the prevalence rates ranging from 15% to 20% in children and 10% in adults.3 The impact of AD on patients' quality of life cannot be overstated, as it often leads to allergic rhinitis and asthma, a phenomenon referred to as the atopic march.4 In addition, AD places a heavy financial burden on healthcare systems worldwide due to its high medical costs, making it the most economically burdensome skin disease. In recent decades, the incidence and prevalence of AD have shown a worrying upward trend. This increase is largely due to environmental factors, including exposure to air pollutants and the widespread use of household hygiene products.5,6 These environmental stimuli contribute to the complex pathogenesis of AD, which is characterized by an exaggerated immune response mainly mediated by T helper type 2 (Th2) cells. Th2 cells are known to produce various cytokines that promote inflammation, such as interleukin (IL)-4 and IL-13, leading to the characteristic symptoms of AD. Biologics such as anti-IL-4 or anti-IL-13 antibodies have been approved for use in patients with moderate to severe AD, but limitations such as the development of resistance and high costs still exist.7 Therefore, it is necessary to develop a new AD therapy based on a deeper understanding of the pathophysiology of AD to minimize the side effects and provide complete disease remission.

In recent years, a growing body of evidence has supported the idea that skin barrier dysfunction plays a critical role in the initiation and progression of AD.8 The skin's epidermal barrier function relies primarily on the outermost layer of the epidermis, which is composed of terminally differentiated keratinocytes.9 To form a robust and intact epidermal barrier, keratinocytes undergo a highly regulated process of differentiation. They gradually progress from the stratum basale (SB) layer to the stratum spinous (SS) layer, stratum granular (SG) layer, and finally to the stratum corneum (SC) layer of the epidermis.10 In AD patients, skin lesions are characterized by a severe impairment of the terminal differentiation of keratinocytes in the SC layer. This is accompanied by an expansion of cells in the SB layer and a reduction of cells in the SS and SG layers.11 The failure of terminal differentiation in keratinocytes leads to a decrease in skin barrier proteins, such as filaggrin (FLG) and loricrin (LOR), in typical skin lesions of AD patients.12 In addition, keratinocytes have the ability to produce specific inflammatory chemokines and cytokines as well. Among these, thymic stromal lymphopoietin (TSLP), produced particularly by keratinocytes, plays a critical role in the pathogenesis of AD.13 TSLP is not detectable in normal or diseased skin, but its expression is significantly increased in the acute and chronic lesions of AD patients. TSLP acts on dendritic cells to create a microenvironment that induces the differentiation of inflammatory Th2 cells.14 In addition, TSLP has been found to stimulate mast cells, leading to the production of high levels of Th2 cytokines through the activation of mouse double minute 2 (MDM2) and signal transducer and activator of transcription 6 (STAT6).15 Keratinocytes are also an important source of other cytokines, such as IL-25 and IL-33, in skin lesions. These cytokines have a profound effect on T cells and contribute to the pathogenesis of various skin diseases.13 Taken together, these studies suggest that keratinocytes are important regulatory and executive cells in AD pathogenesis, but the mechanism underlying AD-induced differentiation blockade and inflammatory cytokine production in keratinocytes is poorly understood.

Recent studies have revealed a fascinating discovery about the skin lesions of AD patients. These lesions were found to have a specific high-salt (sodium chloride) microenvironment compared with the normal skin of AD patients and skin lesions of other skin diseases, such as psoriasis. This suggests that the localized high-salt microenvironment is an exclusive feature of AD lesions.16 This localized high-salt microenvironment in AD lesions may indeed play a significant role in the initiation and development of AD. Further research has shown that the high levels of sodium chloride (NaCl) in the AD microenvironment can trigger the differentiation of Th0 cells into Th2 cells by activating the transcription factor nuclear factor of activated T cells 5 (NFAT5), and this activation of Th2 cells exacerbates disease progression.16 However, the impact of this local high-NaCl microenvironment on keratinocytes, the predominant cell type in the epidermis, remains unclear. In this study, we aimed to shed light on this aspect and discovered that the high NaCl microenvironment in AD indeed inhibited keratinocyte differentiation. In addition, NaCl induced the production of inflammatory cytokines, which further promoted disease progression.

We investigate the underlying mechanisms and find that NaCl activates the signal transducer and activator of transcription 3 (STAT3) signaling pathway through the Serum and glucocorticoid regulated kinase 1 (SGK-1)–mammalian target of rapamycin (mTOR) pathway, leading to the suppression of keratinocyte differentiation and decreases in production of epidermal barrier proteins. Furthermore, this activation of SGK-1–mTOR also leads to increased production of inflammatory cytokines derived from keratinocytes due to activation of NF-κB. Excitingly, we also identified an SGK-1 inhibitor, GSK 650394, that could counteract the inhibitory effect of NaCl on keratinocyte differentiation and cytokine secretion both in vitro and in vivo. Furthermore, GSK 650394 exhibited a synergistic effect when combined with the clinically available pan-JAK inhibitor delgocitinib to alleviate AD-like dermatitis in vivo.

In conclusion, our findings provide critical insights into the role of the high-salt microenvironment in promoting the development of AD through activation of the SGK-1–mTOR pathway in keratinocytes. This opens up opportunities for the development of novel therapeutic interventions targeting this pathway and highlights the potential of combining SGK-1 and JAK inhibitors for the treatment of AD.