Revising Acne Pathogenesis: Inflammation, Genetics, and the Microbiome

Conclusions

• The traditional acne model is incomplete or wrong, because hyperkeratinization and C. acnes overgrowth alone do not convincingly explain inflammatory papules and pustules.
• Acne papules and pustules are better understood as a primarily inflammatory, follicular-based disorder than as a simple infectious disease.
• Host genetics contribute to acne risk, but the genetics are polygenic and unlikely to yield a single straightforward predictive test or target.
• A major genetic signal in acne appears to involve pathways related to surrounding fibroblasts and lipid/inflammatory biology rather than keratinocytes alone.
• Acne lesions contain unusual immune features, including specialized macrophages and fibroblast-driven innate immune responses that help shape inflammation.
• Isotretinoin likely works in part by altering lipid and inflammatory pathways, and this mechanism may inspire safer, more targeted therapies with similar efficacy.
• C. acnes abundance is not necessarily increased in acne, but specific strains and strain behavior differ and may matter more than total bacterial load.
• Inflammatory potential in C. acnes can be influenced by plasmids and by hypoxic follicular conditions that shift bacterial metabolism toward pro-inflammatory products.
• The follicular microbiome works as a community, with C. acnes and S. epidermidis together producing stronger inflammatory and toxic effects than either organism alone.
• These findings support future acne treatments aimed at specific cytokines, enzymes, microbial products, probiotics, vaccines, and other targeted approaches rather than broad assumptions about keratinization or infection.