Dataset Information

Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis.

ABSTRACT:

Background

Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD).

Objective

We aimed to investigate the role of NKT cells in AD development, especially in skin.

Methods

Global proteomic and transcriptomic analyses were performed by using skin and blood from human healthy-controls and patients with AD. Levels of CXCR4 and CXCL12 expression in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4⁺ NKT cells was further evaluated in models of mice with AD by using CXCR4-conditionally deficient or CXCL12 transgenic mice.

Results

CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4⁺ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4⁺ and CD69⁺. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the liver, spleen, and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4⁺ NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4⁺ tissue-resident NKT cells/CXCL12⁺ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD.

Conclusions

CXCR4⁺ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.

SUBMITTER: Sun Z

PROVIDER: S-EPMC9272812 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Atopic dermatitis (AD), also known as atopic eczema, is one of the most common skin diseases and is characterized by allergic skin inflammation, redness, and itchiness and is associated with a hyperactivated type 2 immune response. The leading causes of AD include an imbalance in the immune system, genetic predisposition, or environmental factors, making the development of effective pharmacotherapies complex. Steroids are widely used to treat AD; however, they provide limited efficacy in the long term and can lead to adverse effects. Thus, novel treatments that offer durable efficacy and fewer side effects are urgently needed. Here, we investigated the therapeutic potential of Huangbai Liniment (HB), a traditional Chinese medicine, using an experimental AD mouse model, following our clinical observations of AD patients. In both AD patient and the mouse disease model, HB significantly improved the disease condition. Specifically, patients who received HB treatment on local skin lesions (3-4 times/day) showed improved resolution of inflammation. Using the 1-Chloro-2,4-dinitrobenzene (DNCB)-induced AD model in BALB/c mice, we observed that HB profoundly alleviated severe skin inflammation and relieved the itching. The dermatopathological results showed markedly reversed skin inflammation with decreased epidermal thickness and overall cellularity. Correspondingly, HB treatment largely decreased the mRNA expression of proinflammatory cytokines, including IL-1β, TNF-α, IL-17, IL-4, and IL-13, associated with declined gene expression of IL-33, ST2, and GATA3, which are connected to the type 2 immune response. In addition, HB restored immune tolerance by promoting regulatory T (TREG) cells and inhibiting the generation of TH1, TH2, and TH17 cells in vitro and in the DNCB-induced AD mouse model. For the first time, we demonstrate that HB markedly mitigates skin inflammation in AD patients and the DNCB-induced AD mouse model by reinvigorating the T cell immune balance, shedding light on the future development and application of novel HB-based therapeutics for AD.