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Acne vulgaris, a chronic inflammatory skin disease with a high prevalence worldwide, necessitates reliable preclinical models for both understanding its pathogenesis and evaluating potential anti-acne therapies. This study aims to establish a robust mouse model using intracutaneous injection of Cutibacterium acnes bacterial suspension. Three hairless mouse strains (SKH-hr1, SKH-hr2 brown, and SKH-hr2 + ApoE) were systematically compared to ascertain the stains most closely resembling acne in humans. Various assessments, including photo documentation, biophysical evaluation, blood analysis, and histopathology, were conducted. Despite all strains exhibiting acne-like lesions, SKH-hr1 mice emerged as the most suitable model, demonstrating the most satisfactory results across multiple criteria. This research underscores the significance of employing hairless mice strains as models in acne studies to enhance and facilitate the development of effective therapeutic interventions., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cutibacterium acnes is a commensal bacterium on the skin that is generally well-tolerated, but different strain types have been hypothesized to contribute to the disease acne vulgaris. To understand how some strain types might contribute to skin inflammation, we generated a repository of C. acnes isolates from skin swabs of healthy subjects and subjects with acne and assessed their strain-level identity and capacity to stimulate cytokine release. Phylotype II K-type strains were more frequent on healthy and nonlesional skin of subjects with acne than those isolated from lesions. Phylotype IA-1 C-type strains were increased on lesional skin compared with those on healthy skin. The capacity to induce cytokines from cultured monocyte-derived dendritic cells was opposite to this action on sebocytes and keratinocytes and did not correlate with the strain types associated with the disease. Whole-genome sequencing revealed a linear plasmid in high-inflammatory isolates within similar strain types that had different proinflammatory responses. Single-cell RNA sequencing of mouse skin after intradermal injection showed that strains containing this plasmid induced a higher inflammatory response in dermal fibroblasts. These findings revealed that C. acnes strain type is insufficient to predict inflammation and that carriage of a plasmid could contribute to disease., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Cutibacterium species such as C. acnes, C. avidum, and C. granulosum are known anaerobic skin inhabitants and often cause surgical site infections. These species are genetically similar and are difficult to identify rapidly. In addition, their pathogenicity and antimicrobial resistance remain unknown. In this study, antimicrobial resistance in Cutibacterium isolates was studied and a multiplex PCR method for their identification was developed., Methods: A total of 497 C. acnes, 71 C. avidum, and 25 C. granulosum strains which were isolated from the acne pustule and infectious regions, were used., Results: The antimicrobial resistance rates of C. acnes, C. avidum, and C. granulosum strains isolated from patients with acne vulgaris were higher than those of strains isolated from patients with infectious diseases. In particular, macrolide-clindamycin-resistant strains were isolated most frequently from all species. Among the resistant strains, strains with 23S rRNA mutations were the most common in C. acnes (24.3%, 71/292), whereas C. avidum and C. granulosum strains were most frequently found with erm(X). For the first time, a C. granulosum strain carrying pTZC1, which codes erm(50) and tet(W), was isolated from patients with acne vulgaris. Regarding the rapid identification of causative pathogens from infectious regions, three Cutibacterium species were identified with 100% sensitivity and specificity using multiplex PCR method., Conclusions: Our data showed that antimicrobial resistance differed among Cutibacterium species. The multiplex PCR method may contribute to the rapid detection of Cutibacterium species and selection of appropriate antimicrobial agents., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Although evidence supports that the acne microbiome harbors a diverse range of microbes that play a vital role in the progression of acne vulgaris, the culturable microbes in the acne microbiome have not yet been largely identified. Here, we grew microbe colonies from entire acne lesions on agar plates and identified abundant Staphylococcus, Acinetobacter, and Pseudomonas species from forty selected single colonies. Staphylococcus species, including Staphylococcus epidermidis (S. epidermidis), Staphylococcus hominis (S. hominis), and Staphylococcus aureus (S. aureus), were isolated from tryptic soy broth (TSB) agar plates. However, Cutibacterium acnes (C. acnes) was predominately isolated from furazolidone-supplemented TSB agar plates. Results from gas chromatography-mass spectrometry (GC-MS) analysis revealed that, besides acetate, propionate and butyrate were the main short-chain fatty acids (SCFAs) in fermentation metabolites of C. acnes and S. epidermidis isolates, respectively. The culturable bacteria and SCFA profiles presented in this study provide a reservoir for selecting acne probiotics and developing SCFA-associated therapies against acne vulgaris., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Antimicrobial resistance has become increasingly common across the globe, claiming more than 33,000 lives annually in Europe and 35,000 lives in the United States alone. The problem lies in trying to find potential solutions capable of tackling resistance and being able to fight infections that may resist various antimicrobials. Since Alexander Fleming's discovery in 1928, every antimicrobial synthesized in the past 70 years has developed at least one or more strains of resistant bacteria. One particular alternative to antimicrobials has brought hope to many in the scientific community: the bacteriophage. Bacteriophages are viruses that can replicate within bacteria, triggering genetic alterations and changes in pathways of protein expression by encoding a few to hundreds of genes within their genomes. The bacteriophage can hijack the cell, using the cell's genetic apparatus to replicate within the bacterium until bacterial lysis occurs. This therapy has been used in the genodermatosis Netherton syndrome, which has been associated with the increased risk of Staphylococcus aureus infections. Emerging data support the potential role of bacteriophage therapy for Cutibacterium acnes in acne vulgaris, with a potential role in genetic disorders with severe acne vulgaris, including Apert syndrome. Bacteriophages hold benefits for genodermatoses associated with recurrent cutaneous infections, that is, the immunodeficiencies with distinctive cutaneous features as well as conditions such as atopic dermatitis, in which bacterial colonization plays a strong role., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Gram-positive anaerobic bacterium Cutibacterium acnes (C. acnes) is a commensal of the human skin, but also an opportunistic pathogen that contributes to the pathophysiology of the skin disease acne vulgaris. C. acnes can form biofilms; cells in biofilms are more resilient to antimicrobial stresses. Acne therapeutic options such as topical or systemic antimicrobial treatments often show incomplete responses. In this study we measured the efficacy of nanosecond pulsed electric fields (nsPEF), a new promising cell and tissue ablation technology, to inactivate C. acnes. Our results show that all tested nsPEF doses (250 to 2000 pulses, 280 ns pulses, 28 kV/cm, 5 Hz; 0.5 to 4 kJ/ml) failed to inactivate planktonic C. acnes and that pretreatment with lysozyme, a naturally occurring cell-wall-weakening enzyme, increased C. acnes vulnerability to nsPEF. Surprisingly, growth in a biofilm appears to sensitize C. acnes to nsPEF-induced stress, as C. acnes biofilm-derived cells showed increased cell death after nsPEF treatments that did not affect planktonic cells. Biofilm inactivation by nsPEF was confirmed by treating intact biofilms grown on glass coverslips with an indium oxide conductive layer. Altogether our results show that, contrary to other antimicrobial agents, nsPEF kill more efficiently bacteria in biofilms than planktonic cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The microbiome represents a vast resource for drug discovery, as its members engage in constant conflict to outcompete one another by deploying diverse strategies for survival. Cutibacterium acnes is one of the most common bacterial species on human skin and can promote the common disease acne vulgaris. By employing a combined strategy of functional screening, genetics, and proteomics we discovered a strain of Staphylococcus capitis (S. capitis E12) that selectively inhibited growth of C. acnes with potency greater than antibiotics commonly used in the treatment of acne. Antimicrobial peptides secreted from S. capitis E12 were identified as four distinct phenol-soluble modulins acting synergistically. These peptides were not toxic to human keratinocytes and the S. capitis extract did not kill other commensal skin bacteria but was effective against C. acnes on pig skin and on mice. Overall, these data show how a member of the human skin microbiome can be useful as a biotherapy for acne vulgaris., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Our understanding of the microbiome and the role of Propionibacterium acnes in skin homeostasis and acne pathogenesis is evolving. Multiple methods for sampling and identifying the skin's microbiome exist, and understanding the differences between the abilities of various methods to characterize the microbial landscape is warranted. This study compared the microbial diversity of samples obtained from the cheeks of 20 volunteers, collected by surface swab, pore strips, and cyanoacrylate glue follicular biopsy, all sequenced with 16S rRNA sequencing (V1-V3) and whole-genome metagenomic sequencing. The sequencing method of choice influenced the detection of microbial profiles as whole-genome sequencing captured more species diversity, including viruses, compared with 16S sequencing. The relative abundance of bacterial or fungal species and overall diversity did not differ between sampling methods. However, the viral composition of the skin's surface is unique compared with the follicle, suggesting distinct viral niches within the skin. P. acnes bacteria, ribotypes, and bacteriophages were identified equally by all sampling methods indicating that the sampling method, whether for the skin's surface or follicle, does not impact P. acnes-related characterization and that all may be equally useful for acne-related research studies., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Acne vulgaris is an inflammatory disease occurring in the pilosebaceous unit and is the most common skin condition in young people. A gram-positive bacterium, Propionibacterium acnes, has been suspected to contribute to the development of acne. Here, we report that P. acnes constitutively releases extracellular vesicles (EVs) exhibiting typical EV morphology and size. Moreover, the P. acnes-derived EVs (PEVs) can induce acne-like phenotypes in human epidermal keratinocytes and a reconstituted human skin model. PEVs significantly induced inflammatory cytokines IL-8 and GM-CSF and dysregulated epidermal differentiation by increasing proliferating keratinocytes and decreasing epidermal keratin 10 and desmocollin 1 levels. PEVs showed strong effects, evoking these responses at earlier time points compared with P. acnes extract at the same protein concentration. We verified that PEVs were internalized via clathrin-dependent endocytosis into keratinocytes and that PEV-induced cellular responses occurred via Toll-like receptor 2-dependent signal cascades. Furthermore, PEVs showed a stronger effect than keratinocytes in inducing inflammatory cytokines in myeloid cells. Collectively, our study suggests that PEVs induce acne-like phenotypes in a unique way; therefore, inhibiting the release of EVs from P. acnes or targeting PEV-mediated signaling pathways could represent an alternative method for alleviating acne occurrence and phenotypes., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Acne is a multifactorial skin disease, underpinned by colonization of Propionibacterium acnes and inflammation. The emergence of resistant P. acnes strains has affected the current acne treatment algorithm. This setback served as an impetus for rationally designing a library of next-generation antibiotics that exhibit a bactericidal effect on resistant P. acnes and exert an immunomodulatory function to reduce inflammation. In silico screening showed that one of the molecules, VCD-004, exhibits improved mode of binding to bacterial DNA gyrase. VCD-004 shows high potency against clinical isolates of resistant P. acnes and excellent efficacy in vivo. Furthermore, VCD-004 exhibits a superior mutant prevention index, suggesting that it impedes the development of resistance better than clindamycin. Additionally, it shows optimal skin penetration and has a potent anti-inflammatory effect via reduction of proinflammatory cytokines (IL-6) independent of its antibacterial action. VCD-004 affects P. acnes-induced nuclear accumulation of NF-κB in THP-1 cells. The in vitro viability of human keratinocytes in the presence of VCD-004 indicates a desirable therapeutic window for topical use. Such rationally designed bactericidal and immunomodulatory dual pharmacophore-based lipophilic molecule(s) can emerge as the next-generation topical therapy for acne with underlying resistant P. acnes etiology., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The skin supports a delicate ecosystem of microbial elements. Although the skin typically acts as a barrier, these microbes interact with the internal body environment and imbalances from the "healthy" state that have been linked to several dermatologic diseases. Understanding the changes in microbial flora in disease states allows for the potential to treat by restoring equilibrium. With the rising popularity of holistic and natural consumerism, prebiotics, probiotics, symbiotic, and other therapies are under study to find alternative treatments to these skin disorders through manipulation or supplementation of the microbiome., (Copyright © 2018. Published by Elsevier Inc.)

Propionibacterium acnes is a dominant member of the cutaneous microbiota. Herein, we evaluate the effects of different P. acnes strains and propionic acid on autophagy in keratinocytes. Our results showed that P. acnes strain 889 altered the architecture of the mitochondrial network; elevated the levels of microtubule-associated protein 1 light chain 3B-II, Beclin-1, and phospho-5'-adenosine-monophosphate-activated protein kinase α; stimulated autophagic flux; facilitated intracellular redistribution of microtubule-associated protein 1 light chain 3B; increased average number of autophagosomes per cell; and enhanced development of acidic vesicular organelles in the HPV-KER cell line. Propionic acid increased the level of phospho-5'-adenosine-monophosphate-activated protein kinase α, enhanced lipidation of microtubule-associated protein 1 light chain 3B, stimulated autophagic flux, and facilitated translocation of microtubule-associated protein 1 light chain 3B into autophagosomes in HPV-KER cells. P. acnes strains 889 and 6609 and heat-killed strain 889 also stimulated autophagosome formation in primary keratinocytes to varying degrees. These results indicate that cell wall components and secreted propionic acid metabolite of P. acnes evoke mitochondrial damage successively, thereby triggering 5'-adenosine-monophosphate-activated protein kinase-associated activation of autophagy, which in turn facilitates the removal of dysfunctional mitochondria and promotes survival of keratinocytes. Thus, we suggest that low-level colonization of hair follicles with noninvasive P. acnes strains, by triggering a local increase in autophagic activity, might exert a profound effect on several physiological processes responsible for the maintenance of skin tissue homeostasis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Agak et al. demonstrate that different strains of Propionibacterium acnes, a bacterium colonizing pilosebaceous units in healthy skin and acne, have the ability to induce T helper type 17 cells secreting either IFN-γ or IL-10 and exhibiting either pathogenic or protective properties, respectively. This work contributes to growing evidence indicating that the phenotype of T helper type 17 cells is largely dependent on their microbiological environment., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Studies of the human skin microbiome suggest that Propionibacterium acnes strains may contribute differently to skin health and disease. However, the immune phenotype and functions of T helper type 17 (Th17) cells induced by healthy (P H ) versus acne (P A ) skin-associated P. acnes strains are currently unknown. We stimulated peripheral blood mononuclear cells from healthy donors and observed that P A strains induce higher IL-17 levels than P H strains. We next generated P H and P A strain-specific Th17 clones and show that P. acnes strains induce Th17 cells of varied phenotype and function that are stable in the presence of IL-2 and IL-23. Although P H - and P A -specific clones expressed similar levels of LL-37 and DEFB4, only P H -specific clones secreted molecules sufficient to kill P. acnes. Furthermore, electron microscopic studies showed that supernatants derived from activated P H and not P A -specific clones exhibited robust bactericidal activity against P. acnes, and complete breaches in the bacterial cell envelope were observed. This antimicrobial activity was independent of IL-26, because both natural IL-26 released by Th17 clones and rhIL-26 lacked antimicrobial potency against P. acnes. Overall, our data suggest that P. acnes strains may differentially modulate the CD4 + T-cell responses, leading to the generation of Th17 cells that may contribute to either homeostasis or acne pathogenesis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Acne vulgaris is a chronic inflammatory skin condition classified by the Global Burden of Disease Study as the eighth most prevalent disease worldwide. The pathophysiology of the condition has been extensively studied, with an increase in sebum production, abnormal keratinization of the pilosebaceous follicle, and an inflammatory immune response all implicated in its etiology. One of the most disputed points, however, is the role of the gram-positive anaerobic bacterium Propionibacterium acnes in the development of acne, particularly when this organism is also found in normal sebaceous follicles of healthy skin. Against this background, we now describe the different sampling strategies that have been adopted for qualitative and quantitative study of P acnes within intact hair follicles of the skin and discuss the strengths and weaknesses of such methodologies for investigating the role of P acnes in the development of acne., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The human commensal bacterium Propionibacterium acnes (P. acnes) resides in the pilosebaceous duct of the skin. It has been long implicated in the pathogenesis of acne, although its exact role in the development of inflammatory acne lesions and in the formation of the microcomedo in the early stages of acne remains controversial. The worldwide prevalence of antibiotic-resistant P. acnes is increasing, with rates varying in different parts of the world. The reason for the difference in the antibiotic resistance patterns of P. acnes among different countries is not clear, although it may be attributed to different antibiotic prescribing habits, concomitant use of topical agents (retinoids, benzoyl peroxide, or other antibiotics), varying methods of bacterial sampling, or even different P. acnes populations. Although the relative abundances of P. acnes may be similar among patients with acne and individuals without acne, P. acnes populations and the presence of P. acnes biofilms differ, with different potential virulence properties and antimicrobial resistance patterns. Implications of the use of antibiotics and of antimicrobial resistance in patients with acne include the decreased efficacy of antibiotic treatments for acne, and the possible emergence of other resistant bacterial species via selective pressure by antibiotic use., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Growing interest in microbial contributions to human health and disease has increasingly led investigators to examine the microbiome in both healthy skin and cutaneous disorders, including acne, psoriasis, and atopic dermatitis. The need for common language, effective study design, and validated methods is critical for high-quality standardized research. Features, unique to skin, pose particular challenges when conducting microbiome research. This review discusses microbiome research standards and highlights important factors to consider, including clinical study design, skin sampling, sample processing, DNA sequencing, control inclusion, and data analysis., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Propionibacterium acnes is a skin commensal bacterium that contributes to the development of acne vulgaris and other infections. Recent work revealed that P. acnes clinical isolates can be classified into distinct phylotypes, several of which have associations with healthy skin or acne. We sought to determine if these phylotypes induce different immunological responses and express protein factors that may contribute to their disease associations. We found that acne-associated P. acnes phylotypes induced 2- to 3-fold higher levels of IFN-γ and IL-17 in peripheral blood mononuclear cells compared with healthy phylotypes. On the other hand, P. acnes phylotypes associated with healthy skin induced 2- to 4-fold higher levels of IL-10. Comparative proteomic analysis of P. acnes phylotypes revealed a differential expression of several proteins, including an adhesion protein that was expressed at least 10-fold higher in acne-associated phylotypes and a cell surface hydrolase expressed in all phylotypes except those associated with healthy skin. Taken together, our data provide insight into how specific P. acnes phylotypes influence immune responses and the pathogenesis of acne., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Benzoyl peroxide (BPO), a therapeutic agent for acne vulgaris, was assessed for in vitro antimicrobial activity against Propionibacterium acnes using a novel broth microdilution testing that improved BPO solubility. We searched for a suitable culture medium to measure the minimum inhibitory concentration (MIC) of BPO against P. acnes and finally found the Gifu anaerobic medium (GAM) broth supplemented with 0.1(v/v)% glycerol and 2(v/v)% Tween 80, in which BPO dissolved up to 1250 μg/mL and P. acnes grew well. The MICs and minimum bactericidal concentrations (MBCs) of BPO against 44 clinical isolates of P. acnes collected from Japanese patients with acne vulgaris were determined by our testing method using the supplemented GAM broth. The MICs of BPO were 128 or 256 μg/mL against all isolates of P. acnes regardless of susceptibility to nadifloxacin or clindamycin. The MBCs of BPO were also 128 or 256 μg/mL against the same isolates. Moreover, BPO at the MIC showed a rapid bactericidal activity against P. acnes ATCC11827 in time-kill assay. In conclusion, we could develop a novel assay for the MIC and MBC determinations of BPO against P. acnes, which is reliable and reproducible as a broth microdilution testing and the present results suggest that BPO has a potent bactericidal activity against P. acnes., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Aims: Propionibacterium acnes has been considered to influence the acne lesions. The present study intended to elucidate the underlying signaling pathways of P. acnes in human sebaceous gland cells relative to the generation of proinflammatory cytokines., Main Methods: Cell-free extracts of P. acnes under stationary growth phase were co-incubated with human immortalized SZ95 sebocytes. Then, cell-free P. acnes extracts-induced cytokine expression was evaluated by measuring mRNA and protein levels using quantitative RT-PCR and ELISA. Changes of phosphorylated cell signaling proteins and transcription factors were measured by Western blots and Milliplex assay. The interactive molecular mechanisms of P. acnes and sebocytes were examined through use of shRNA and the specific inhibitors of signaling pathways., Key Findings: Cell-free extracts of P. acnes significantly stimulated secretion of interleukin (IL)-8 and IL-6 in SZ95 sebocytes. The degradation of IκB-α and increased phosphorylation of IκB-α, p38 mitogen activated protein kinase (MAPK), CREB, and STAT3 were demonstrated. Quantitative RT-PCR measurements revealed that gene expression of IL-8 and Toll-like receptor 2 (TLR2) was enhanced by cell-free extracts of P. acnes. In addition, the NF-κB inhibitor BMS345541, p38 MAPK inhibitor SB203580, or anti-TLR2 neutralizing antibody prevented cell-free P. acnes extracts-induced secretion of IL-8. Knockdown of TLR2 using shRNA exerted similar inhibitory effects on IL-8 expression. Moreover, inhibition of STAT3 activity by STA-21 enhanced P. acnes-mediated secretion of IL-8., Significance: Cell-free extracts of P. acnes are capable to activate NF-κB and p38 MAPK pathways and up-regulate secretion of IL-8 through TLR2-dependent signaling in human SZ95 sebocytes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Protease-activated receptor-2 (PAR-2) functions as innate biosensor for proteases and regulates numerous functions of the skin. However, the expression and physiological role of PAR-2 in sebocytes remain to be elucidated. Here, we identified PAR-2 expression in SZ95 sebocytes at both mRNA and protein levels. Intracellular Ca(2+) mobilization by PAR-2 agonist peptide (PAR-2 AP) or Propionibacterium acnes (P. acnes) culture supernatant was detected, indicating that P. acnes is a potent activator of PAR-2 on sebocytes. The small interfering RNA (siRNA)-mediated PAR-2 knockdown in sebocytes resulted in defective differentiation and lipogenesis. PAR-2 AP treatment enhanced lipogenesis and sterol response element-binding protein-1 (SREBP-1) expression, suggesting a role of PAR-2 in the differentiation and lipogenesis of sebocytes. Moreover, PAR-2 AP induced cytokines and human β-defensin-2 (hBD-2) transcription in sebocytes. PAR-2 expression was increased in sebaceous glands of acne lesions. PAR-2 silencing by siRNA abrogated the increase in sebaceous lipogenesis and SREBP-1 expression by P. acnes supernatant. PAR-2 knockdown also inhibited the P. acnes supernatant-induced expression of cytokines and hBD-2. In conclusion, PAR-2 is expressed in SZ95 sebocytes and mediates differentiation, lipogenesis, inflammation, and innate immunity in response to P. acnes. Therefore, PAR-2 might be a therapeutic target for sebaceous gland disorders such as acne.

Aims: The present study was designed to evaluate the therapeutic potential of antimicrobial photodynamic therapy (PDT) using chlorin e6 with halogen light against acne bacteria-induced inflammation., Main Methods: Highly purified chlorin e6 (Ce6), as a second generation photosensitizer, was synthesized from Spirulina chlorophyll. To evaluate the antimicrobial property of Ce6-mediated PDT with halogen light, the broth microdilution method and two-color fluorescence assay were used. The free radicals generated upon irradiating Ce6 with halogen light were measured using 2,7-dichlorofluorescin diacetate. Propionibacterium acnes was intradermally injected into the left ear of the ICR mice, and the anti-inflammatory effect of Ce6-mediated PDT with halogen light was measured by the histological examination. The expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) as well as pro-inflammatory cytokines were also measured by Western blotting., Key Findings: Chlorin e6-mediated PDT with halogen light (30,000 lx) inactivated various skin bacteria, including P. acnes in a dose-dependent manner. The MIC99 value against P. acnes (KCTC3314) of Ce6 with light was >0.49 μg/ml, whereas the MIC99 for Ce6 alone was >31.25 μg/ml. Ce6-mediated PDT suppressed the expression of P. acnes-induced pro-inflammatory cytokines and iNOS, but not COX-2 in a mouse model., Significance: This study showed a remarkable therapeutic effect of chlorin e6-mediated PDT with halogen light against P. acnes-induced inflammation. Our results suggest for the first time the potential of Ce6-mediated PDT with halogen light as a more effective and safer alternative treatment to antibiotic therapy against pathogenic infections of the skin., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Propionibacterium acnes is a Gram-positive commensal bacterium thought to be involved in the pathogenesis of acne vulgaris. Although the ability of P. acnes in the initiation of pro-inflammatory responses is well documented, little is known about adaptive immune responses to this bacterium. The observation that infiltrating immune cells consist mainly of CD4(+) T cells in the perifollicular space of early acne lesions suggests that helper T cells may be involved in immune responses caused by the intra-follicular colonization of P. acnes. A recent report showing that P. acnes can induce IL-17 production by T cells suggests that acne might be a T helper type 17 (Th17)-mediated disease. In line with this, we show in this work that, in addition to IL-17A, both Th1 and Th17 effector cytokines, transcription factors, and chemokine receptors are strongly upregulated in acne lesions. Furthermore, we found that, in addition to Th17, P. acnes can promote mixed Th17/Th1 responses by inducing the concomitant secretion of IL-17A and IFN-γ from specific CD4(+) T cells in vitro. Finally, we show that both P. acnes-specific Th17 and Th17/Th1 cells can be found in the peripheral blood of patients suffering from acne and, at lower frequencies, in healthy individuals. We therefore identified P. acnes-responding Th17/Th1 cells as, to our knowledge, a previously unreported CD4(+) subpopulation involved in inflammatory acne.

Propionibacterium acne and sebaceous glands are considered to have an important role in the development of acne. Although information regarding the activation of innate immunity by P. acnes in the sebaceous gland is limited, different P. acnes phylotypes and a higher prevalence of follicular P. acnes macrocolonies/biofilms in sebaceous follicles of skin biopsies from acne compared with control skin and occasionally single P. acnes clusters in single sebaceous glands have been detected. In this study, we investigated whether P. acnes activates the inflammasome in human sebaceous glands in vivo and in vitro. We found that IL-1β expression was upregulated in sebaceous glands of acne lesions. After stimulation of human sebocytes with P. acnes, the activation of caspase-1 and secretion of IL-1β were enhanced significantly. Moreover, knocking down the expression of NLRP3 abolished P. acnes-induced IL-1β production in sebocytes. The activation of the NLRP3 inflammasome by P. acnes was dependent on protease activity and reactive oxygen species generation. Finally, we found that NALP3-deficient mice display an impaired inflammatory response to P. acnes. These results suggest that human sebocytes are important immunocompetent cells that induce the NLRP3 inflammasome, and that P. acnes-induced IL-1β activation in sebaceous glands may have a role in combating skin infections and in acne pathogenesis.

Propionibacterium acnes colonizes the lipid-rich sebaceous glands of the skin. This preferential anaerobic bacterium is easily identified if cultures are prolonged. It is involved in the inflammation process of acne, but until recently, it was neglected in other clinical presentations. Despite a reported low virulence, the new genomic, transcriptomic, and phylogenetic studies have allowed better understanding of this pathogen's importance that causes many chronic and recurrent infections, including orthopedic and cardiac prosthetic, and breast or eye implant-infections. These infections, facilitated by the ability of P. acnes to produce a biofilm, require using anti-biofilm active antibiotics such as rifampicin. The antibiogram of P. acnes is not systematically performed in microbiology laboratories because of its susceptibility to a wide range of antibiotics. However, in the last 10 years, the rate of antibiotic-resistant bacteria has increased, especially for macrolides and tetracyclines. Recently, rpoB gene mutations conferring resistance to rifampicin have been also reported. Thus in case of a biofilm growth mode, the therapeutic strategy should be discussed, according to the resistance phylotype and phenotype so as to optimize the treatment of these severe infections., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Acne vulgaris is potentially a severe skin disease associated with colonization of the pilo-sebaceous unit by the commensal bacterium Propionibacterium acnes and inflammation. P. acnes is considered to contribute to inflammation in acne, but the pathways involved are unclear. Here we reveal a mechanism that regulates inflammatory responses to P. acnes. We show that IL-1β mRNA and the active processed form of IL-1β are abundant in inflammatory acne lesions. Moreover, we identify P. acnes as a trigger of monocyte-macrophage NLRP3-inflammasome activation, IL-1β processing and secretion that is dependent on phagocytosis, lysosomal destabilization, reactive oxygen species, and cellular K+ efflux. In mice, inflammation induced by P. acnes is critically dependent on IL-1β and the NLRP3 inflammasome of myeloid cells. These findings show that the commensal P. acnes-by activating the inflammasome-can trigger an innate immune response in the skin, thus establishing the NLRP3-inflammasome and IL-1β as possible therapeutic targets in acne.

Acne vulgaris is the most common skin disorder affecting millions of people worldwide and inflammation resulting from the immune response targeting Propionibacterium acnes has a significant role in its pathogenesis. In this study, we have demonstrated that P. acnes is a potent inducer of T helper 17 (Th17) and Th1, but not Th2 responses in human peripheral blood mononuclear cells (PBMCs). P. acnes stimulated expression of key Th17-related genes, including IL-17A, RORα, RORc, IL-17RA, and IL-17RC, and triggered IL-17 secretion from CD4(+), but not from CD8(+) T cells. Supernatants from P. acnes-stimulated PBMCs were sufficient to promote the differentiation of naive CD4(+)CD45RA T cells into Th17 cells. Furthermore, we found that the combination of IL-1β, IL-6, and transforming growth factor-β-neutralizing antibodies completely inhibited P. acnes-induced IL-17 production. Importantly, we showed that IL-17-expressing cells were present in skin biopsies from acne patients but not from normal donors. Finally, vitamin A (all-trans retinoic acid) and vitamin D (1,25-dihydroxyvitamin D3) inhibited P. acnes-induced Th17 differentiation. Together, our data demonstrate that IL-17 is induced by P. acnes and expressed in acne lesions and that both vitamin A and D could be effective tools to modulate Th17-mediated diseases such as acne.

The human skin microbiome has important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that although the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne, and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, we identified potential genetic determinants of various P. acnes strains in association with acne or health. Our analysis suggests that acquired DNA sequences and bacterial immune elements may have roles in determining virulence properties of P. acnes strains, and some could be future targets for therapeutic interventions. This study demonstrates a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases. It underscores the importance of strain-level analysis of the human microbiome to define the role of commensals in health and disease.

For two centuries, Koch's postulates have set the gold standard for establishing the microbiological etiology of infection and disease. Genomic sequencing now brings finer resolution to both bacterial strain variation and the host genetic state that may predispose to disease. In this issue of the JID, Fitz-Gibbons and colleagues present strain-based resolution of Propionibacterium acnes and its association with the common teenage malady acne vulgaris. Here I examine how Koch's postulates were envisioned and incorporate this finer resolution of both host and microbial states.

Acne vulgaris is a highly prevalent skin disorder characterized by hyperseborrhea, inflammation, and Propionibacterium acnes overgrowth. Only isotretinoin and hormonal therapy reduce sebum production. To identify a new drug candidate that modulates sebum, we examined the effects of EGCG, the major polyphenol in green tea, on human SEB-1 sebocytes and in patients with acne. In SEB-1 sebocytes, we found that EGCG reduced sebum by modulating the AMPK-SREBP-1 signaling pathway. EGCG also reduces inflammation by suppressing the NF-κB and AP-1 pathways. EGCG also induces cytotoxicity of SEB-1 sebocytes via apoptosis and decreases the viability of P. acnes, thus targeting almost all the pathogenic features of acne. Finally, and most importantly, EGCG significantly improved acne in an 8-week randomized, split-face, clinical trial, and was well tolerated. Our data provide a therapeutic rationale for the use of EGCG in acne.

Tretinoin (TRE) or all-trans retinoic acid is employed in the topical treatment of various skin diseases including acne and psoriasis. However, its use is strongly limited by side effects and high chemical instability. TRE encapsulation in nanostructured systems reduces these problems. Chitosan is a biopolymer that exhibits a number of interesting properties such as bioadhesion and antibacterial activity. The aim of this work was to prepare and characterize solid lipid nanoparticles (SLN) containing TRE, with and without addition of chitosan, to assess their in vitro cytotoxicity in keratinocytes and to evaluate their antibacterial activity against bacteria related to acne. SLN without (SLN-TRE) and with (SLN-chitosan-TRE) chitosan were prepared by hot high pressure homogenization. The hydrodynamic mean diameter and zeta potential were 162.7±1.4 nm and -31.9±2.0 mV for SLN-TRE, and 284.8±15.0 nm and 55.9±3.1 mV for SLN-chitosan-TRE. The SLN-chitosan-TRE exhibited high encapsulation efficiency, high physical stability in the tested period (one year), were not cytotoxic to keratinocytes and showed high antibacterial activity against P. acnes and S. aureus. Therefore chitosan-SLN can be good candidates to encapsulate TRE and to increase its therapeutic efficacy in the topical treatment of acne., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Sophorolipids (SLs) are known to possess antimicrobial properties towards many species (particularly Gram-positive, or Gram(+)) of bacteria. However, these properties can only be exerted if the SLs can be introduced to the bacterial cells in an acceptable manner. Propionibacterium acnes is the common bacterial cause of acne. It is a Gram(+) facultative anaerobe that is susceptible to the antimicrobial effects of SLs. In this study we demonstrated that different biopolymer matrices could be used to produce SL composite films that exert various antimicrobial efficiencies against P. acnes. Increasing SL concentrations in poly-3-hydroxybutyrate (PHB) and PHB-co-10%-3-hydroxyhexanoate (PHB/HHx) resulted in noticeably improved (PHB/HHx was best) antimicrobial activity based on the size of the zones of inhibition using an overlay plating technique on synthetic growth medium. However, increasing concentrations of SLs in PHB and PHB/HHx films also increased film opacity, which diminishes the appeal for use especially in visible (facial) areas. Pectin and alginate improved the transparent character of SL composite films while also acting as successful carriers of SLs to P. acnes. The lactone form of the SLs proved to exhibit the best antimicrobial action and in concert with either pectin or alginate biopolymers provided a comparatively transparent, successful means of utilizing SLs as a renewable, environmentally benign anti-acne solution., (Published by Elsevier B.V.)

Propionibacterium acnes has a major role in the development of acne lesions. IGF-1 stimulates the proliferation of keratinocytes via an activation of the IGF-1 receptor (IGF-1R). Zinc has been proven to work efficiently against inflammatory acne and to modulate the IGF-1 system. Our objectives were to study the modulation of IGF-1 and IGF-1R expression by P. acnes extracts and to determine their modulation by zinc gluconate. In vivo, we analyzed biopsies of acne lesions and healthy skin, and in vitro we used skin explants incubated with two P. acnes extracts--membrane fraction (MF) and cytosolic proteins--with or without zinc. IGF-1 and IGF-1R expression was evaluated using immunohistochemistry, and the IGF-1 production in supernatants was measured by ELISA. Then, IGF-1 and IGF-1R mRNA levels were analyzed using quantitative PCR on normal human epidermal keratinocytes (NHEKs). IGF-1 and IGF-1R were overexpressed in acne lesions. MF increased IGF-1 and IGF-1R expression in the epidermis of explants and was associated with an overexpression of both Ki-67 and filaggrin. Zinc had the effect of downregulating IGF-1 and IGF-1R levels. These observations were confirmed at the mRNA level for IGF-1R in NHEKs. These results demonstrate that P. acnes can induce the formation of comedones by stimulating the IGF/IGF-1R system. Moreover, zinc downregulates this pathway.

Acne is a multifactorial chronic disease affecting around 80% of teenage population. The pathogenesis of acne involves inflammatory reactions and colonization by the Propionibacterium acnes (P. acnes) strain. P. acnes stimulates the keratinocytes involved in the innate immune response, the intensity of which could be influenced either by bacterial intrinsic factors or by endogenous factors of the host., (Copyright © 2010. Published by Elsevier SAS.)

Various sebum free fatty acids (FFAs) have shown antibacterial activity against a broad range of gram-positive bacteria, resulting in the suggestion that they are accountable, at least partially, for the direct antimicrobial activity of the skin surface. In this study, we examined the effects of sebum FFAs on the antimicrobial peptide (AMP)-mediated innate immune defense of human sebocytes. Incubation of lauric acid, palmitic acid, or oleic acid (OA) with human sebocytes dramatically enhanced their expression of human beta-defensin (hBD)-2, one of the predominant AMPs found in the skin, whereas remarkable increases in hBD-1, hBD-3, and human cathelicidin LL-37 were not observed. Secreted hBD-2 was detectable by western blotting in the supernatant of sebocyte culture incubated with each FFA, but not with a vehicle control. The supernatant of FFA-incubated sebocyte culture showed antimicrobial activity against Propionibacterium acnes, whereas the enhanced antimicrobial activity of human sebocytes was neutralized by anti-hBD-2 IgG. In addition, the FFA-induced hBD-2 expression was suppressed by blocking the cluster of differentiation (CD)36 fatty acid translocase on the surface of sebocytes with anti-human CD36 IgG or blocking the NF-kappaB signaling pathway with BMS-345541, a highly selective inhibitor of inhibitory kappaB kinase. These data suggest that sebum FFAs upregulate the expression of hBD-2 in human sebocytes, which may enhance the disinfecting activity of the human sebaceous gland. The FFA-induced upregulation of hBD-2 is facilitated by CD36-mediated FFA uptake and NF-kappaB-mediated transactivation. The upregulation of mouse beta-defensin 4, a mouse ortholog for hBD-2, was also observed in the hair follicle sebaceous glands of mouse ear skin after an epicutaneous application of OA, the most hBD-2-inducible FFA tested. This report highlights the potential of using FFAs as a multifunctional antimicrobial therapy agent for acne vulgaris treatment; FFAs may provide direct antibacterial activities against P. acnes and enhance the skin's innate antibacterial defense by inducing the expression of hBD-2 in sebocytes as well.

We have come a long way since 1896, when it was first suggested that Propionibacterium acnes, found in acne lesions, was the cause of acne. Although several lines of evidence suggest the direct role of P acnes in acne, the mechanism by which P acnes contributes to the pathogenesis of acne is debated. The importance of P acnes in the induction and maintenance of the inflammatory phase of acne has been established. Emerging data that inflammatory events occur in the very earliest stages of acne development have reopened the debate about the potential involvement of this microorganism in comedogenesis and acne initiation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Increased sebum secretion has been known as one of the major pathogenic factors in the development of acne; however, objective sebum measurement methods have been developed only recently. We have limited information about the association of sebum secretion, and the development of acne. There continues to be controversy about the role of sebum in the development of acne. This contribution will discuss sebum measurement techniques and the results of recent studies on the relationship of sebum, facial cosmetic skin type, and acne. New therapeutic modalities for inflammatory acne aim to control seborrhea. Superficial chemical peels, laser treatment for inflammatory acne, and photodynamic therapy are used as adjunctive therapies for acne; however, their sebosuppressive effects are only temporary., (Copyright 2010 Elsevier Inc. All rights reserved.)

Contents of bioactive components, free radical scavenging and anti-acne producing bacteria activities of young and mature fruit rind extracts of mangosteen were compared. The young fruit rind extract contained significantly higher contents of phenolics and tannins and promoted higher free radical scavenging activity than the mature fruit rind extract, while the later extract contained higher contents of flavonoids and alpha-mangostin xanthone and gave higher anti-acne producing bacteria activity than the young fruit rind extract. Thus, the young and mature stages of mangosteen fruit rind should be beneficial for further development of antioxidant and anti-acne pharmaceutical preparations, respectively.

Background: Acne vulgaris is a multifactorial inflammatory disease of the sebaceous follicles of the face and torso that frequently occurs in adolescence. Initially, acne starts as a non-inflammatory comedo. Subsequently, inflammatory reactions evolve to pustules, granulomas and cystic lesions. Many pathogenic mechanisms have been proposed including sebum excretion, obstruction of hair follicles, impaired keratinization of hair epithelium, bacterial overgrowth and immunological mechanisms; the role of Propionibacterium acnes (P. acnes) is particularly important. Facultative anaerobic gram-positive rods have been implicated in acne pathogenesis. However, the host immune response to P. acnes has not been as yet elucidated., Objectives: The aim of the present study is to evaluate the importance of the immune response to P. acnes and the bacteriological factor in the pathogenesis of acne., Methods: P. acnes isolated from acne lesions and healthy volunteers skin were cultured. The peripheral blood mononuclear cells (PBMC) from acne patients or healthy volunteers were stimulated with viable P. acnes, and cytokine production was evaluated using RT-PCR and ELISA., Results: IFN-gamma, IL-12p40, and IL-8 mRNA and protein production were significantly increased in PBMC from acne patients compared to that from normal donors. However, different P. acnes species isolated from acne lesions or normal subjects showed no difference in cytokines production from acne patients and normal subjects PBMC., Conclusions: The inflammatory response of acne appears to be attributable to P. acnes-induced host immune response rather than P. acnes strains from normal skin or acne lesions.

Propionibacterium acnes (P. acnes) is a commensal microorganism found in sebum-rich skin and plays a role in acne inflammation by stimulating keratinocyte to produce a number of proinflammatory cytokines. However, the role of P. acnes in the dermis of acne lesions, where tissue remodeling after inflammation eventually takes place, is not known. In this study, we investigated whether P. acnes induces matrix metalloproteinase (MMP), a key enzyme involved in matrix remodeling in human dermal fibroblasts (hDF). We found that P. acnes increased expression of pro-matrix metalloproteinase (proMMP)-2 mRNA/protein in hDF, but not that of proMMP-9. Concomitantly, P. acnes induced tumor necrosis factor-alpha (TNF-alpha) mRNA/protein expression in hDF, which in turn increases both proMMP-2 mRNA and protein expression. P. acnes induced such changes through the activated NF-kappaB pathway. Doxycycline was found to inhibit the expression of proMMP-2 induced either by P. acnes or TNF-alpha. These results suggest that P. acnes stimulates hDF to produce TNF-alpha, which mediates the expression of proMMP-2 through the NF-kappaB pathway. The secretion of proMMP-2 from hDF upon P. acnes stimulation may contribute to the pathogenesis of tissue remodeling in acne skin.

Sertaconazole nitrate is an antifungal agent that exhibits anti-inflammatory activity; however, the mechanism for this action was unknown. We investigated the cellular mechanisms by which sertaconazole exerts its anti-inflammatory activity in keratinocytes and human peripheral blood mononuclear cells (PBMCs). Paradoxically, sertaconazole was found to activate the proinflammatory p38 mitogen-activated protein kinase. Treatment with sertaconazole also resulted in the induction of cyclooxygenase-2 (COX-2) and the subsequent release of prostaglandin E2 (PGE2). Knocking down p38 in keratinocytes using small interfering RNA resulted in an inhibition of sertaconazole-induced PGE2 release confirming that activation of p38 was required for PGE2 production. Additionally, in stimulated keratinocytes and human PBMCs, sertaconazole was found to suppress the release of cytokines. Treatment with anti-PGE2 antiserum or the COX-2 inhibitor NS398 reversed the inhibitory effects of sertaconazole on the release of proinflammatory cytokines, linking endogenous PGE2 with the anti-inflammatory effects. Finally, in an in vivo mouse model of tetradecanoyl phorbol acetate (TPA)-induced dermatitis, the sertaconazole-mediated inhibition of TPA-induced ear edema was reversed by NS398. Biochemical analysis of tissue biopsies revealed increase in PGE2 levels in sertaconazole-treated mice. Thus, activation of the p38-COX-2-PGE2 pathway by agents such as sertaconazole provides anti-inflammatory therapeutic benefits.

The present study was aimed to investigate the activity of Thai medicinal plants on inflammation caused by Propionibacterium acnes in terms of free radical scavenging and cytokine reducing properties. P. acnes have been recognized as pus-forming bacteria triggering an inflammation in acne. Antioxidant activity was determined by DPPH scavenging and NBT reduction assay. The result showed that Garcinia mangostana possessed the most significant antioxidant activity and reduced reactive oxygen species production. Houttuynia cordata, Eupatorium odoratum, and Senna alata had a moderate antioxidant effect. In addition, Garcinia mangostana extracts could reduce the TNF-alpha production as determined by ELISA. Garcinia mangostana was highly effective in scavenging free radicals and was able to suppress the production of pro-inflammatory cytokines. This study has identified the promising source of anti-inflammatory agent which could be useful in treatment of acne vulgaris.

Propionibacterium acnes plays an important role in the pathogenesis of acne vulgaris, a common disorder of the pilosebaceous follicles. Recently, it was suggested that P. acnes cells residing within the follicles grow as a biofilm. In the present study, we tested the biofilm-forming ability of several P. acnes strains in a microtiter plate model. We also evaluated the resistance of biofilm-grown P. acnes towards antimicrobial agents commonly used in the treatment of acne and the production of putative virulence factors. Our results indicate that P. acnes can form biofilms in vitro. The results also show that sessile P. acnes cells are more resistant to various commonly used antimicrobial agents than planktonic cells. In addition, sessile cells produce more extracellular lipases as well as significant amounts of the quorum-sensing molecule autoinducer-2.