Introduction
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease characterized by impaired skin barrier function and excessive immune responses within the skin1. While type 2 inflammation is a central feature of AD and the target of several established therapies, increasing evidence suggests that myeloid cells also contribute to the initiation and amplification of cutaneous inflammation2. We observed increased expression of an activating receptor on circulating myeloid cells from patients with AD compared with healthy controls, while skin transcriptomic datasets also indicated elevated receptor expression in AD skin. We therefore investigated whether this receptor amplifies inflammation in AD and whether interfering with this pathway can reduce disease severity.
Methods
Receptor expression in lesional skin from patients with AD was assessed by immunofluorescence microscopy. In primary human blood monocytes, receptor activation was examined by measuring secretion of the pro-inflammatory cytokines IL-1β, IL-6 and TNFα following receptor stimulation. These responses were modulated using either a ligand-binding inhibitory peptide or a receptor-blocking antibody. In vivo, we used the MC903-induced model of AD-like skin inflammation in C57BL/6 and BALB/c mice. Disease severity was evaluated by clinical assessment of skin inflammation and ear swelling as well as by histological measurement of epidermal thickening. Immune-cell populations and inflammatory gene expression were further characterized by flow cytometry and NanoString-based gene expression profiling. Pharmacological interference with receptor activation was complemented by experiments in mice genetically lacking the receptor.
Results
In lesional skin from patients with AD, receptor expression was increased in CD68+ myeloid cells within the dermis, supporting the presence of this pathway directly within inflamed human skin. In primary human blood monocytes, receptor stimulation increased secretion of IL-1β, IL-6 and TNFα, whereas both the inhibitory peptide and receptor-blocking antibody attenuated this inflammatory response. In the MC903-induced mouse model, pharmacological interference with receptor activation reduced disease severity in both C57BL/6 and BALB/c mice. Treated animals showed reduced ear swelling and crust formation as well as decreased epidermal hyperplasia. In BALB/c mice, in which skin redness could be assessed more reliably, treatment additionally reduced erythema. In C57BL/6 mice, treatment also reduced serum IgE levels. Flow-cytometric analysis further indicated modest treatment-associated shifts in immune-cell populations. Gene expression profiling showed that MC903 induced a broad inflammatory program in both mouse strains, involving myeloid activation, chemokine signalling and epithelial stress responses. Treatment with the inhibitory peptide attenuated this program and reduced expression of key mediators, including Il1b, Il6, Cxcl9, Cxcl10, and S100a8/a9. Finally, mice genetically lacking the receptor developed markedly reduced crusting and ear thickness, independently supporting a disease-promoting role of this pathway.
Discussion
Together, these findings identify the activating myeloid receptor as an important amplifier of cutaneous inflammation in AD. Its increased expression in dermal myeloid cells in lesional skin from patients with AD supports its relevance to human disease, while experiments with primary human circulating blood monocytes demonstrate that receptor activation can directly enhance pro-inflammatory cytokine production. In vivo, both pharmacological interference with receptor activation in two mouse strains and genetic deletion of the receptor resulted in milder MC903-induced skin inflammation, providing complementary evidence for its contribution to disease development. Gene expression profiling further indicates that this effect extends beyond visible disease symptoms and affects broader inflammatory networks within the skin. Targeting such an upstream amplifier may therefore offer an opportunity to dampen several inflammatory pathways simultaneously. In particular, local inhibition of receptor activation may offer a therapeutic strategy to control skin inflammation while minimizing systemic interference with immune function.
1. Weidinger, S., Aoiki, V., Dhar, S., Dlova, N. C., Kabashima, K., Ma, L., Flohr, C. & Irvine, A. D. Atopic dermatitis. Nature Reviews Disease Primers 2026 12:1 12, 36- (2026).
2. Kupschke, E. & Schenk, M. The myeloid switch: immune drivers in atopic dermatitis — roles in pathogenesis and emerging therapeutic targeting. Front. Immunol. 16, 1608338 (2025).