ABSTRACT / PROJECT SUMMARY Research Project The overall goal of UCLA/UCSD Research Project is to investigate the interaction between the microbiome, lipid metabolism and the host immune response in acne. The microbiome of the pilosebaceous unit (PSebU), the initial site where acne lesions develop, is tractable, with Cutibacterium acnes the dominant bacterium. C. acnes is considered to be one of the key contributing factors in the pathogenesis of acne. The UCLA/UCSD Research Project is based on our recent findings using transcriptomics, metagenomics and lipidomics, establishing the goal to link together these diverse biologic responses into a model that may explain the pathogenesis of acne. By applying single cell RNA-sequencing (scRNA-seq) and spatial-seq, the Modlin and Gallo labs have together identified specific macrophage and mesenchymal stem cell fibroblasts subpopulations that occur in acne lesions as compared to uninvolved skin from the same patients. Surprisingly, we detected a large population of TREM2 macrophages, previously identified in diseases characterized by altered lipid metabolism, in acne lesions expressing both lipid metabolism and pro-inflammatory gene programs. We found that squalene, a component of sebum, induced TREM2 macrophages in vitro that were not antimicrobial, in part because squalene inhibited production of and scavenged oxygen radicals that kill C. acnes. Furthermore, acne lesions also contain a unique inflammatory fibroblast subpopulation that undergoes an adipogenic trajectory and produces pro-inflammatory cathelicidin in a TLR2 dependent manner, implicating for the first time the perifollicular fibroblast as a critical contributor to acne inflammation. The UCLA/UCSD Research Project (Modlin, Gallo), “Acne: a disease of lipid metabolism, microbiome and the immune response”, will initially focus studies on the role of TREM2 macrophages and adipogenic fibroblasts in the pathogenesis of acne. The project investigators will obtain acne biopsy specimens (Hata, Kim), then address the link between the immune response in acne lesions to the microbiome and lipid metabolism. The Research Project will be supported by a UCLA Bioinformatics Core (Pellegrini, Yang) to analyze scRNA-seq and spatial-seq of acne lesions, a UCSD Microbiology and Metagenomics Core (Gallo, O’Neill) to isolate and characterize C. acnes strains, and lipidomics analysis (Bensinger, UCLA) of biopsy specimens and key cell types derived in vitro. Ultimately, Bioinformatics core will use mergeomics to combine data from transcriptomics, metagenomics and lipidomics to create a network model of the pathogenesis of acne. The proposed studies will provide new insights into how lipid metabolism and the skin microbiome shapes cutaneous immune responses contributing to inflammation, with the potential for intervention in skin disease.