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- Title
Antimicrobial production by perifollicular dermal preadipocytes is essential to the pathophysiology of acne.
- Authors
O'Neill, Alan M.; Liggins, Marc C.; Seidman, Jason S.; Do, Tran H.; Li, Fengwu; Cavagnero, Kellen J.; Dokoshi, Tatsuya; Cheng, Joyce Y.; Shafiq, Faiza; Hata, Tissa R.; Gudjonsson, Johann E.; Modlin, Robert L.; Gallo, Richard L.
- Abstract
Innate immune defense against deep tissue infection by Staphylococcus aureus is orchestrated by fibroblasts that become antimicrobial when triggered to differentiate into adipocytes. However, the role of this process in noninfectious human diseases is unknown. To investigate the potential role of adipogenesis by dermal fibroblasts in acne, a disorder triggered by Cutibacterium acnes, single-cell RNA sequencing was performed on human acne lesions and mouse skin challenged by C. acnes. A transcriptome consistent with adipogenesis was observed within specific fibroblast subsets from human acne and mouse skin lesions infected with C. acnes. Perifollicular dermal preadipocytes in human acne and mouse skin lesions showed colocalization of PREF1, an early marker of adipogenesis, and cathelicidin (Camp), an antimicrobial peptide. This capacity of C. acnes to specifically trigger production of cathelicidin in preadipocytes was dependent on TLR2. Treatment of wild-type mice with retinoic acid (RA) suppressed the capacity of C. acnes to form acne-like lesions, inhibited adipogenesis, and enhanced cathelicidin expression in preadipocytes, but lesions were unresponsive in Camp−/− mice, despite the anti-adipogenic action of RA. Analysis of inflamed skin of acne patients after retinoid treatment also showed enhanced induction of cathelicidin, a previously unknown beneficial effect of retinoids in difficult-to-treat acne. Overall, these data provide evidence that adipogenic fibroblasts are a critical component of the pathogenesis of acne and represent a potential target for therapy. Acne in action: Adipogenesis plays a key role during deep tissue infection with Staphylococcus aureus, but the contribution of this process in acne caused by Cutibacterium acnes is not well understood. O'Neill et al. demonstrate that adipogenesis in skin fibroblasts is critical to acne pathogenesis. In mice and humans, perifollicular dermal preadipocytes were a subset of fibroblasts that showed colocalization of the PREF1 adipogenesis marker with the antimicrobial peptide cathelicidin upon exposure to C. acnes in a TLR2-dependent manner. Retinoic acid treatment of wild-type mice promoted enhanced cathelicidin expression, inhibited adipogenesis, and suppressed acne-like lesion formation, and acne patients undergoing retinoid treatment also showed induction of cathelicidin. These data indicate that adipogenic fibroblasts are critical to acne pathogenesis.
- Subjects
CUTIBACTERIUM acnes; ANTIMICROBIAL peptides; STAPHYLOCOCCUS aureus infections; ACNE; PATHOLOGICAL physiology
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 632, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abh1478