Analysis of intracellular communication reveals consistent gene changes associated with early-stage acne skin

• Published in: Cell communication and signaling 2024-08, Vol.22 (1), p.400-18
• Main Authors: Deng, Min, Odhiambo, Woodvine O, Qin, Min, To, Thao Tam, Brewer, Gregory M, Kheshvadjian, Alexander R, Cheng, Carol, Agak, George W
• Format: Article
• Language: English
• Subjects: Acne; Acne vulgaris; Acne Vulgaris - genetics; Acne Vulgaris - metabolism; Acne Vulgaris - pathology; B cells; Cell activation; Cell interaction; Cell interactions; Cell-cell communication; Cells; Cellular signal transduction; Chemokines; Communication; Comparative analysis; Computer software industry; Cutibacterium acnes; Datasets; Dermatitis; Development and progression; Developmental stages; Female; Fibroblasts; Gene expression; Genes; Genetic aspects; Genetic research; Homeostasis; Humans; Inflammation; Interleukin 13; Interleukin-13 Receptor alpha1 Subunit - genetics; Interleukin-13 Receptor alpha1 Subunit - metabolism; Intracellular signalling; Keratinocytes; Keratinocytes - metabolism; Keratinocytes - pathology; Ligands; Lymphocytes; Macrophages; Macrophages - metabolism; Male; Medical research; Medicine, Experimental; Psoriasis; RNA sequencing; Signal distribution; Signal transduction; Signal Transduction - genetics; Single cell and spatial transcriptomic sequencing; Skin; Skin - metabolism; Skin - pathology; Skin diseases; Smooth muscle; Transcription activation; Wound healing
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-024-01725-4

A comprehensive understanding of the intricate cellular and molecular changes governing the complex interactions between cells within acne lesions is currently lacking. Herein, we analyzed early papules from six subjects with active acne vulgaris, utilizing single-cell and high-resolution spatial RNA sequencing. We observed significant changes in signaling pathways across seven different cell types when comparing lesional skin samples (LSS) to healthy skin samples (HSS). Using CellChat, we constructed an atlas of signaling pathways for the HSS, identifying key signal distributions and cell-specific genes within individual clusters. Further, our comparative analysis revealed changes in 49 signaling pathways across all cell clusters in the LSS- 4 exhibited decreased activity, whereas 45 were upregulated, suggesting that acne significantly alters cellular dynamics. We identified ten molecules, including GRN, IL-13RA1 and SDC1 that were consistently altered in all donors. Subsequently, we focused on the function of GRN and IL-13RA1 in TREM2 macrophages and keratinocytes as these cells participate in inflammation and hyperkeratinization in the early stages of acne development. We evaluated their function in TREM2 macrophages and the HaCaT cell line. We found that GRN increased the expression of proinflammatory cytokines and chemokines, including IL-18, CCL5, and CXCL2 in TREM2 macrophages. Additionally, the activation of IL-13RA1 by IL-13 in HaCaT cells promoted the dysregulation of genes associated with hyperkeratinization, including KRT17, KRT16, and FLG. These findings suggest that modulating the GRN-SORT1 and IL-13-IL-13RA1 signaling pathways could be a promising approach for developing new acne treatments.