Cutibacterium acnes induce lipid accumulation and antimicrobial responses in fibroblasts

Summary: Abstract Body: The pathogenesis of acne involves complex interactions between Cutibacterium acnes (C. acnes) and various skin cells. Our findings show that C. acnes significantly induce lipid accumulation in fibroblasts, an effect observed in keratinocytes in our prior work. Exposure to 15% C. acnes supernatant increased Oil Red O (ORO) staining, showing a twofold increase by day 2, threefold by day 4, and fivefold by day 8 (p<0.0001) in 3T3 fibroblasts, indicating sustained lipid accumulation. Treatment with propionic acid, the main short-chain fatty acid produced by C. acnes, also increased lipid accumulation in 3T3 cells by threefold (p<0.0001) in ORO staining. Using differential mobility spectrometry-based shotgun lipidomic analysis and liquid chromatography–mass spectrometry, we observed that exposure to 15% C. acnes supernatant for 4 days significantly induced a twofold increase in ceramides, phospholipids, fatty acids, and triglycerides. In addition to lipid accumulation, C. acnes stimulated the production of antimicrobial factors, including lipocalin-2 (lcn2) and cathelicidin antimicrobial peptide (cramp) in 3T3 fibroblasts. Notably, LCN2 exhibited a bactericidal activity, killing C. acnes at 45 μg/ml. For the first time, we demonstrate that Pdgfra-Cre+/- Camp flox/flox mice exhibit accelerated resolution of acne lesions in an acne model, with lesion resolution occurring twice as quickly. This is associated with a reduction in lipid staining by Bodipy following C. acnes injections combined with squalene application. These findings position fibroblasts as critical players in skin lipid metabolism and immunity, suggesting new therapeutic targets to regulate skin barrier function and immune responses. Samia Almoughrabie¹, Kevin Williams^{2, 3}, Brigitte Closs⁴, Elodie Aymard⁴, Steven J Besinger^{3, 5, 6}, Richard L. Gallo¹ 1. Dermatology, University of California San Diego, La Jolla CA,, San Diego, CA, United States. 2. Biological Chemistry, Los Angeles, CA, United States. 3. UCLA Lipidomics Lab, Los Angeles, CA, United States. 4. SILAB, Brive, France. 5. Microbiology, Immunology and Molecular Genetics, Los Angeles, CA, United States. 6. University of California Los Angeles Department of Molecular and Medical Pharmacology, Los Angeles, CA, United States. Innate Immunity, Microbiology, and Microbiome