Cutibacterium acnes induces skin region-specific innate immune memory events in epidermal keratinocytes

Summary: Abstract Body: In immune cells, external insults can cause immune and inflammatory activation. The resulting persistent signaling, metabolic and epigenetic changes can lead to trained immunity, a form of innate immune memory (IIM) in these cells. We investigated whether Cutibacterium acnes (C. acnes) can cause similar changes in human keratinocytes. Normal human epidermal keratinocytes from mammoplasty (NHEK-B) or abdominoplasty (NHEK-A) were trained with C. acnes, followed by a five-day rest period and secondary induction with Pam3CSK4 (TLR1/2 agonist). Immune gene expression (e.g., TNFα, IL-8) revealed regional disparities, signs of innate training-like changes in NHEK-B, and tolerance in NHEK-B cells, compared to untrained, but Pam3CSK4 induced ones. Transcriptome analysis of trained and induced NHEK cells revealed significant differences in the global gene expression patterns. While NHEK-A cells showed changes in gene expressions associated with skin development, NHEK-B cells demonstrated an increased inflammatory response. Region-specific changes in the global genomic 5mC and 5hmC content using ELISA, together with the observed differences in the metabolic changes of NHEK-B and NHEK-A cells in our in vitro model system using high-resolution respirometry, are consistent with the IIM changes similar to what happens in immune cells. Based on the results, we propose that epidermal keratinocytes remember their external influences, and the molecular basis of these events is the induction of skin region-specific immune IIM events. Fanni Balogh^{1, 2, 3}, Anett Magyari², Lilla Erdei^{1, 3}, Blanka Toldi¹, Balázs Koncz⁴, Máté Manczinger^{2, 4}, Laura Bagi⁴, Katalin Burián⁵, Rolland Gyulai², Lajos Kemény^{1, 2, 3}, Kornélia Szabó^{1, 2, 3} 1. HUN-REN–SZTE Dermatological Research Group, Szeged, Hungary. 2. Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary. 3. HCEMM-USZ Skin Research Group, Szeged, Hungary. 4. HCEMM-BRC Systems Immunology Research Group, Synthetic and Systems Biology Unit, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary. 5. Department of Medical Microbiology, University of Szeged, Szeged, Hungary. Innate Immunity, Microbiology, and Microbiome