Sebum-associated type 17 inflammation in atopic dermatitis: a single-cell and in vivo study of body-site immune heterogeneity

Abstract

Summary Background Inflammatory skin diseases exhibit striking anatomical predilections, yet the mechanisms shaping site-specific immune programs remain poorly understood. Although atopic dermatitis (AD) is classically considered a type 2-driven disease, lesions arising in sebum-rich skin such as the face often show suboptimal responses to type 2-targeting biologics, suggesting the presence of distinct site-specific immune programs shaped by the local tissue environment. Methods We performed single-cell RNA sequencing (scRNA-seq) on matched facial and popliteal lesions from adult male patients with AD (n = 3 facial lesions, n = 3 popliteal lesions) to characterize site-specific immune landscapes. MC903-induced AD mouse models were used to investigate the effects of topical sebum on cutaneous inflammation, with mechanistic studies focusing on macrophage lipid metabolism and inflammatory signaling assessed by flow cytometry, quantitative PCR, and pharmacological inhibition approaches. Findings scRNA-seq analysis revealed enhanced type 17–associated immune signatures in facial AD lesions relative to matched popliteal lesions, despite preservation of type 2 inflammatory features. In mouse models, topical sebum selectively amplified Th17 responses through FABP5-dependent induction of macrophage IL-1β production. Sebum also reduced the therapeutic response to Th2 blockade, accompanied by further enhancement of type 17 inflammation. Pharmacological inhibition of FABP5 attenuated sebum-induced immune deviation and reduced disease severity. Interpretation These findings suggest that a sebum-associated macrophage metabolic axis contributes to type 17–skewed inflammation in sebaceous skin regions, providing a mechanistic framework for understanding anatomical immune heterogeneity and highlighting potential targets for modulating site-specific inflammation. Funding The 10.13039/100016698National Natural Science Foundation of China; 10.13039/501100004731Natural Science Foundation of Zhejiang Province; China Postdoctoral Science Foundation; 10.13039/501100003819Natural Science Foundation of Hubei Province; 10.13039/100016966Bethune Charitable Foundation; Wuhan Municipal Natural Science Foundation; Wuhan Municipal Health Commission; The Shanghai Municipal Commission of Health and Family Planning; The 10.13039/501100012247Program of Shanghai Academic/Technology Research Leader.