MIF-driven keratinocyte-macrophage-Th2 axis identified as key inflammatory circuit in atopic dermatitis, inhibited by MIF098

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by immune dysregulation and skin barrier dysfunction. Despite its high prevalence, the precise cellular heterogeneity and complex intercellular communication networks driving AD pathogenesis remain incompletely understood. Current treatments often broadly target immune responses, highlighting a need for therapies that specifically disrupt key inflammatory circuits. Understanding these specific cell-cell interactions, particularly involving cytokines like MIF, could pave the way for more targeted and effective therapeutic strategies.

Researchers employed single-cell RNA sequencing (scRNA-seq) on lesional skin from AD patients to identify cell types and analyze transcriptomic characteristics of keratinocytes, T cells, and macrophages. Intercellular communication networks were mapped to understand cell-cell interactions. Findings were validated using in vitro models, including HaCaT, HEK, primary keratinocytes, and THP-1 cells, and an MC903-induced AD mouse model. MIF expression was quantified via qPCR and Luminex, and macrophage distribution by immunofluorescence staining. Functional studies utilized MIF098 to inhibit MIF signaling in these models.

scRNA-seq revealed significant cellular remodeling in AD lesions, with marked enrichment of keratinocytes, T cells, and macrophages. Specifically, the proportion of Th2 cells was increased, and an MRC1+ macrophage subset (Cluster3-Mac) was uniquely enriched in AD lesions. Intercellular communication analysis demonstrated that proliferative keratinocytes interact with Cluster3-Macrophages via the MIF-CD74/CD44 signaling axis, with keratinocytes acting as senders. Furthermore, MRC1+ macrophages engaged with Th2 cells through PTPRC signaling. Consistent with these findings, MIF expression was significantly upregulated in the serum of AD patients, in IL-13-treated HaCaT and HEK cells, and in epithelial tissues of AD model mice. In the MC903-induced AD mouse model, lesional skin showed epidermal thickening, inflammatory infiltration, and accumulation of M2-polarized macrophages (F4/80+CD206+).

Functional validation using MIF098 demonstrated that inhibition of MIF signaling effectively reduced inflammation in the MC903-induced AD mouse model.