Neutrophil recruitment by CD4 tissue-resident memory T cells induces chronic recurrent inflammation in atopic dermatitis

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that continues to impose significant physical, mental, and economic burdens on patients. Recent research has suggested the significant role of tissueresident memory (TRM) cells in AD. However, the precise role and mechanisms of action of TRM cells in AD remain unclear. A deeper understanding of the involvement of TRM cells in AD will unveil promising pathways for future innovative therapeutic strategies. Methods: To investigate the involvement of TRM cells in AD, we used diverse mouse models and employed experimental techniques to manipulate cell formation and depletion. We assessed the inflammatory response by analyzing mouse ear phenotype, measuring ear thickness, and performing hematoxylin and eosin staining. Flow cytometry and immunofluorescence staining were used to identify different cell types and evaluate changes in cell quantity. Additionally, we used qPCR to analyze gene expression of relevant chemokines and cytokines. Results: Our study revealed the presence of TRM cells in the skin after exposure to calcipotriol. After a 24-h rechallenge, we observed substantial neutrophil infiltration into the previously irritated skin. Neutrophil depletion prior to re-challenge effectively prevented early flare-up responses during AD recurrence. Furthermore, we demonstrate that CD4+TRM cells upregulate expression of cytokines INF-gamma and TNF-alpha, which may induce the expression of CXCL1, thereby recruiting neutrophils and contributing to the chronic recurrent inflammation observed in AD. Conclusions: We have established a novel, chronic recurrent mouse model for investigating TRM cells in AD. Our findings demonstrate that CD4+TRM cells in the skin mediate early flare-up response during AD recurrence and influence the chronic recurrent inflammation of AD by recruiting neutrophils. Targeting CD4+TRM cells may represent a promising approach for the treatment of chronic recurrent inflammation in AD.