Spatial transcriptomics reveal compartmentalized dysregulation of lipid metabolism in acne vulgaris

Summary: Abstract Body: Multiple observations suggest that increased sebaceous lipid synthesis and altered sebum composition contribute to lesional formation in acne vulgaris. However, the signaling pathways by which keratinocytes sense and respond to sebaceous lipids, as well as the epithelial compartments that become perturbed during disease, remain incompletely defined. To study the role of sebaceous-keratinocyte crosstalk in acne vulgaris, we performed Xenium in situ transcriptomics on punch biopsies from patients (comedonal, pustular, and non-lesional) and healthy controls. We find that sebocytes in acne comedonal skin show a transcriptional signature associated with increased sebaceous lipid production (FASNhighAWAT2high), decreased synthesis of glycosphingolipids (FA2Hlow), and upregulated growth factors and inflammatory mediators (CXCL8highTNFhigh). By contrast, in acne pustular lesions, sebaceous lipogenesis is suppressed, suggesting the inflammatory milieu of the acne pustule leads to a localized, temporary shutdown of sebum production. We also demonstrate that epidermal and upper hair follicle keratinocytes in acne lesions have a hyper-keratinizing phenotype (KRT10high) and demonstrate resistance to retinoid signaling as manifested by decreased retinoid receptor expression (RARGlowRXRAlow) and increased expression of fatty acid binding protein 5 (FABP5), which shuttles fatty acid ligands away from retinoid receptors and toward peroxisome proliferator-activated receptors (PPARs). In human N/TERT keratinocytes, we probe the effects of specific sebaceous lipids on FABP5 expression and signaling. Overall, our results suggest a model in which sebum dysregulation promotes retinoid resistance and hyper-keratinization in acne lesional skin. Joseph S. Durgin¹, Thomas Huyge¹, Natalia Veniaminova¹, Yuli Cai¹, Lam C. Tsoi¹, Johann E. Gudjonsson¹, Sunny Wong¹ 1. Dermatology, University of Michigan, Ann Arbor, MI, United States. Translational Studies: Cell and Molecular Biology