In this article we review the most recent findings in acne physiopathology. We focus on specific issues associated with each of the four pathogenic factors, as well as some additional interesting research pathways, which may provide novel frameworks for improving our understanding of the disease pathogenesis and development of new medications. Finally, we provide a brief outlook of the prospects for this intriguing field of dermatology.

The four central factors that contribute to acne physiopathology are inflammation, colonization with P. acnes , increased sebum production and hypercornification of the pilosebaceous duct. Recent research suggests that these factors are much more interrelated than has been previously understood. Novel factors that could contribute to acne physiopathology include inflammasomes, T helper (Th)17 cell immunology, P. acnes sequence type and nutritional factors.

The exact sequence of events and how they are interconnected is still unknown, due to the inherent complexity of this disease. Ongoing research is modifying the classical view of acne pathogenesis through identification of underlying mechanisms for previous theories and experimental findings. Recently, researchers from diverse academic disciplines including dermatology, immunology, microbiology and endocrinology have reported novel concepts for acne physiopathology by employing cutting‐edge experimental methods and academic approaches.

Acne vulgaris is a near universal cutaneous inflammatory disease affecting more than 85% of adolescents worldwide. 1 , 2 While not a fatal disease, acne can persist throughout life and leave permanent scarring on the face as a result. Four distinct processes are believed to play critical roles in the formation of acne lesions: alteration of keratinization processes, leading to comedo formation; follicular colonization by Propionibacterium acnes ; increased sebum production and inflammatory mediators around pilosebaceous units. 3 - 5 Several medications that have been devised to target these pathogenic mechanisms have demonstrated modest efficacy, but their use is also accompanied by potentially serious side‐effects. 6 , 7

To identify the studies included in this review computerized searches were undertaken in the PubMed and Medline databases using the term ‘acne vulgaris’ with the following terms: acne, pathogenesis, inflammation, sebocyte, P. acnes , nutrition and oxidative stress, and combinations of these keywords. Searches were limited to studies published between 1995 and 2014.

It is clear that there are physiopathological influences other than the four classic factors involved in the pathogenesis of acne. However, it is not yet clear exactly what roles they play and their relative importance. With such understanding in place, these could be key areas for therapeutic intervention.

A relationship between oxidative/nitrosative stress and acne has been also reported, suggesting that patients with acne are under increased cutaneous and systemic oxidative stress. Sahib et al . 67 reported significantly higher levels of oxidative stress in patients with acne than in healthy controls, represented by higher levels of serum malondialdehyde (the end product of lipid peroxidation) and lower levels of serum glutathione. Consistent with these findings, activities of antioxidants in the blood (including superoxide dismutase and glutathione peroxidase) have also been found to be significantly lower in patients with acne compared with healthy controls. 68

Large‐scale genetic studies provide valuable information for causative genes, predicting who is prone to acne and acne scarring in the future; three genome‐wide association studies (GWASs) have been published in 2014 alone. Navarini et al . 64 compared severe cases of acne with controls in a U.K.‐based GWAS, which identified three associated loci that all contain genes linked to the TGF‐β signalling pathway. Two other GWASs looking into risk factors in severe acne (in distinct populations) have identified significant associations with other unrelated loci, and together these studies provide the foundation for further research into the genetic basis of acne. 65 , 66

There is increasing evidence that hereditary factors contribute to the pathophysiology of acne, and this evidence is also discussed elsewhere in this supplement. 37 Yaykasli et al . 62 investigated the association of polymorphisms of two important genes involved with extracellular matrix remodelling – matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) – in patients with acne and controls. The CC, CT and TT genotypes for the MMP2 (−1306 C/T) polymorphism were similar between the patient and control groups, while distribution of the GG, GC and CC genotypes for the TIMP2 (−418 G/C) polymorphism were different, suggesting that the TIMP2 genotype could increase the tendency to develop acne. 62 Anis et al . 63 also reported that polymorphisms in the CYP1A1 gene, but not tumour necrosis factor‐α genes, are a risk factor for acne vulgaris.

We strongly believe that further well‐designed clinical and experimental studies that carefully control for the many confounding factors that can arise in diet‐related trials would establish the usefulness of diet control to mitigate overstimulation of mTORC1–S6K1 signalling to improve acne.

Possible further cellular mechanisms to link acne and diet have been proposed by Melnik et al . 57 - 61 based on related studies conducted recently. They demonstrated that acne appears to feature overstimulated mammalian target of rapamycin complex (mTORC)1, a master regulator of cell growth, proliferation and metabolic homeostasis. They showed that mTORC1 signalling in the sebaceous follicle is aggravated by nutrient signals derived from a Western diet. 57 - 61 Forkhead box transcription factor O1, after sensing the nutrient signal, is also known to interact with key regulatory proteins in sebaceous lipogenesis, antagonizing oxidative stress and, more importantly, functioning as a rheostat of mTORC1. 57 - 61 Exaggerated mTORC1 signalling stimulates the kinase S6K1 – an important downstream target in this cascade – which negatively controls insulin signalling at the level of insulin receptor substrate‐1 phosphorylation. 57 , 59

Netea et al . 55 have demonstrated that chocolate consumption primes human blood mononuclear cells from volunteers to release more IL‐1β and IL‐10 upon stimulation with P. acnes , potentially revealing underlying mechanisms for acne aggravation. We also reported that omega‐3 fatty acids and γ‐linolenic acid could improve acne during a 10‐week clinical trial. 56 At final visits (after 10 weeks of intervention), the mean inflammatory acne lesion count was significantly reduced in the omega‐3 group from 10·1 ± 3·2 to 5·8 ± 3·4. A similar change was observed in the γ‐linolenic acid group (9·8 ± 5·2 vs. 6·6 ± 3·7).

As also discussed in the paper by Tan and Bhate 37 elsewhere in this supplement, knowledge of the relationship between the physiopathology of acne and food has been accumulating. In contrast to traditional cross‐sectional survey studies, randomized controlled dietary intervention studies have demonstrated that acne and diet are intricately related. 53 , 54 Our group reported that a reduction in the glycaemic load of the diet for 10 weeks resulted in improvements in acne. 53 The mean numbers of both noninflammatory and inflammatory acne lesions in the group with low‐glycaemic‐load diet significantly decreased by 27·6% and 29·1% from baseline, respectively, which are notable decreases in comparison with those achieved in the control group. In addition to clinical improvements, histopathological analysis revealed decreased inflammation and reduced expression of SREBP‐1 and IL‐8 in the low‐glycaemic‐load group. 53

Selway et al . 52 recently found that TLR2 was expressed in basal and infundibular keratinocytes and sebaceous glands, and its activation triggered the release of IL‐1α from primary human keratinocytes in vitro . Furthermore, they reported that in vitro exposure of microdissected human sebaceous glands to pathogen‐associated molecular patterns specific for TLR2 resulted in a pattern of IL‐1α‐like cornification.

Previously, high levels of the proinflammatory cytokine IL‐1α were reported in acne lesions in vivo , and in vitro work has revealed that exposure of isolated infundibula and pilosebaceous units to IL‐1α induced comedo formation. 12 , 47 , 48 There has been speculation regarding the role of IL‐1α in initial acne formation, and it has been hypothesized that IL‐1α might be released from keratinocytes or immune cells, although no studies on in vivo acne lesions support this theory. 49 - 51

There are clear suggestions of some commonality between the various pathways involved in lipid metabolism in the sebaceous glands. The potential to modulate both TLR2 activity and sebum production by altering the activity of HSD‐11β1 is an interesting proposition.

Although not directly involved with pathogenic processes, the latest basic research assaying therapeutic mechanisms of sebosuppressive medications identifies interesting signal transduction pathways. Nelson et al . 43 , 44 report that tumour necrosis factor‐related apoptosis‐inducing ligand and the neutrophil gelatinase‐associated lipocalin are key proteins in the sebocyte‐specific apoptotic response to 13‐ cis ‐retinoic acid in SEB‐1 sebocytes, which, in part, may be due to the lipid‐rich environment of the sebocyte. Our group notes that activation of the AMP‐activated protein kinase (AMPK) pathway could lead to a decrease in intracellular lipid accumulation by synergistically suppressing sterol regulatory element‐binding proteins (SREBPs), the master regulators of lipid synthesis, in a SEB‐1 sebocyte model. 45 As the central regulator of cellular and organismal metabolism in eukaryotes, the AMPK pathway acutely controls lipid metabolism through phosphorylation of acetyl‐CoA carboxylases, while mediating long‐term adaptive effects through phosphorylation of SREBP‐1, resulting in reduced expression of lipogenic enzymes. 46 Therefore, we strongly believe that modulation of this pathway would provide another opportunity to develop therapeutic strategies to control seborrhoea and thus acne.

McNairn et al . 42 recently reported that the transforming growth factor (TGF)‐β signalling pathway plays an essential role in lipogenesis through sebaceous gland regulation. They found that activation of the TGF‐β signalling pathway is necessary, and sufficient, to maintain sebocytes in an undifferentiated state, resulting in decreased lipid accumulation through the TGF‐β RII–Smad 2‐dependent pathway. 42

11‐β‐Hydroxysteroid dehydrogenase type I (HSD‐11β1), which catalyses the conversion of cortisone into active cortisol, is expressed in sebaceous glands and may modulate glucocorticoid‐induced lipid synthesis and TLR2 signalling. 40 Enhanced expression of HSD‐11β1 in acne‐involved sebaceous glands could implicate glucocorticoids and metabolic pathway enzymes in the regulation of sebaceous gland activity during acne pathogenesis, partly explaining the pathogenesis of both steroid‐ and stress‐related acne. Choi et al . 41 recently found that tumour necrosis factor‐α induces lipogenesis in human sebocytes through the c‐Jun N‐terminal kinase and phosphoinositide‐3‐kinase/Akt pathways. This report is interesting as it indicates that the two distinct pathological processes of lipogenesis and inflammation are directly interconnected.

Meingassner et al . 38 reported that pharmacological inhibition of stearoyl‐CoA desaturase (SCD)1 in mouse skin rapidly triggers pronounced sebaceous gland atrophy after topical applications. SCDs are microsomal enzymes that catalyse the biosynthesis of monounsaturated fatty acids from saturated acetyl‐CoAs. This finding is interesting because it suggests that lipid metabolism could be closely associated with sebaceous gland differentiation. In the same vein, Schuster et al . 39 reported a sebostatic effect of peroxisome proliferator‐activated receptor activators not only by lipogenesis but also by protecting cells from apoptosis and holocrine secretion. Elucidating close relationships between two major functions of sebocytes in vivo – lipogenesis and differentiation for cellular disintegration – would provide another opportunity to regulate sebum secretion.

With respect to the role of hyperseborrhoea in the development of acne lesions, recent studies have focused on pathways that regulate sebaceous gland biology and related androgen metabolism in the development of acne lesions.

Genomics and proteomics are helping to explain how, despite being a commensal bacterium, P. acnes can stimulate an immunological response and how pathogenic forms of the bacterium exist. It is to be hoped that the crossovers between this work and the work of immunologists working to identify inflammatory cytokines involved in the propagation of the immune response will, in time, reveal new therapeutic targets for acne.

When this phenomenon was investigated with P. acnes biofilms in vitro , it was found that sessile cells were more resistant to antimicrobial agents than planktonic cells, and also produced more extracellular lipases. 34 Historically, this process was considered to be a key factor in acne pathogenesis, and these findings have been further supported by the results of a recent study. Using immunofluorescence microscopy to achieve direct visualization of P. acnes in skin biopsies, Jahns et al . demonstrated that extensive P. acnes biofilms are more common in the sebaceous follicles of patients with acne vulgaris compared with controls. 35 , 36 The authors did not find any qualitative differences between P. acnes biofilms in acne and control samples, indicating that phenotypic, rather than genetic, changes associated with biofilm formation may account for the pathogenic role of P. acnes in acne vulgaris. It should also be noted that the presence of the biofilm represents an additional physical barrier for antibiotics, and could partly account for a certain proportion of antibiotic resistance in this patient population. The role of biofilms in the development of acne is discussed in more detail in the paper by Tan and Bhate in this supplement. 37

Biofilm formation is a pathological process during which bacteria irreversibly anchor and grow on a surface, and ultimately produce extracellular polymers that enhance adherence and matrix formation. 33 This process leads to alteration of the phenotype of the bacteria, resulting in changes in growth rate and gene transcription.

Recently, a few eminent microbiology groups have conducted phylogenetic analysis on isolates from patients with defined grades of acne, and from healthy carriers, utilizing more refined DNA‐based typing methods including multilocus sequence typing and metagenomics. 28 - 30 These methods have found that P. acnes consists of phylogenetically distinct cluster groups with various pathogenic characteristics, including differing abilities to elicit inflammation and differing secretome profiles. 31 , 32 Furthermore, it appears that specific sequence types are included within the phylogenetic divisions, and that some P. acnes strains may play an aetiological role in acne, while others are associated with health. This provides a solid framework for evidence‐based research into the exact role of this organism in acne. 28 - 32 As P. acnes is directly associated with factors involved in innate immunity, continuing research in this field will contribute to the evolving paradigm of bacterial aetiology with acne, from association to causality.

The involvement of P. acnes in the pathogenesis of acne is still disputed. 24 , 25 Conflicting opinions arise from the fact that P. acnes is a dominant member of the normal cutaneous flora, while at the same time many in vitro and in vivo studies have shown that it induces inflammatory responses in skin parenchymal cells and immune cells. 26 , 27

However, this is still very much a work in progress. We do not yet have all the answers about the precise mechanisms for the onset of inflammation in acne and we cannot rule out that there may be other cytokines and related molecules involved that could represent further opportunities for clinical intervention.

These recent publications continue to underline the importance of IL‐1β (and the function of the inflammasome), Th2 and Th17/IL‐17 in the development of acne, provide some understanding of how existing medication works and make some suggestions for new interventional strategies based on attacking these targets.

The Kim group first suggested that Th17 cells may play a role in acne pathogenesis. 13 , 22 These authors reported that P. acnes is a potent inducer of genes related to IL‐17 and IL‐22 in human peripheral blood mononuclear cells. Additional work by the same authors provided further support for the clinical relevance of these findings by identifying IL‐17‐positive cells in skin biopsies of typical closed comedo‐type acne lesions. 22 Their observations suggest that the immune response in acne is not uniquely Th1 mediated and thus may be more complex than previously thought. Furthermore, the authors demonstrate that vitamin A and vitamin D inhibited P. acnes ‐induced Th17 differentiation, suggesting possible therapeutic roles for these vitamins. Further studies are needed to link the in vitro effects of P. acnes on IL‐17 expression in monocytes to the progression of inflammation in acne lesions over time. 23

In addition to the role played by the innate immune system, it is well known that the adaptive immune system also plays a central role in inflammation. A key response is the recruitment of activated Th1 lymphocytes leading to early acne lesions. 17 - 19 Th17 cells are also potent inducers of tissue inflammation, particularly in the pathogenesis of psoriasis. 20 , 21

Recent advances in our understanding of innate immunity in skin diseases offer an opportunity to delve deeper into the reciprocal interactions of the host and P. acnes in patients with acne.

Traditionally, it was thought that P. acnes induced inflammatory cytokines and metalloproteinases through activation of the Toll‐like receptor (TLR)‐2 signalling pathway. 13 , 14 Dispenza et al . 15 recently reported that, in a group of patients with acne, circulating monocytes expressed higher levels of TLR2, and isolated monocytes secreted more TLR2. TLR4 was downregulated in response to P. acnes stimulation compared with the control group. Sahdo et al . 16 also found that P. acnes strongly activates the inflammasome in human peripheral neutrophils, and that the response to P. acnes isolated from different sources varied significantly, almost fivefold. These two interesting studies strongly suggest that acne is characterized by perturbation of innate immune signalling in response to P. acnes , and further suggest that the alteration in immune response in acne extends beyond the skin.

Qin et al . 8 reported a potential role for inflammasome activation in P. acnes ‐induced inflammation. In their histological analysis, the authors detected mature caspase‐1 and NLRP3 – molecules associated with proteasomes – around the follicles of the pilosebaceous unit, which are colocalized with tissue macrophages. This suggests that P. acnes is a proteasome activator, triggering the production of the key inflammatory mediator, interleukin (IL)‐1β, via the NLRP3 inflammasome and the caspase‐1 activation pathway. 8 These findings were supported by those of Kistowska et al . 9 , who independently reported that sensing of P. acnes is a crucial event in the exacerbation of acne inflammation via a mechanism involving NLRP3–inflammasome activation in myeloid cells.

Recently, several groups have reported a potential role for innate immunity in acne pathogenesis, focusing on inflammasome activation. 8 - 11 These reports are important because they provide possible evidence of the triggers that initiate inflammation – one of the first pathogenic steps leading to disease manifestation. 12

Outlook and future perspectives

Despite the fact that acne is the most common skin disease, it is clear that there are missing pieces in its puzzling physiopathology. Recent advances from interdisciplinary academic approaches have provided an important, more fundamental perspective on the whole spectrum of acne physiopathology. Increased understanding of the disease will help in the development of novel therapies directed against the pathogenesis of acne. The outlook and future perspectives for acne treatment based on recent developments in this field can be summarized as follows.

Firstly, a profound understanding of innate and adaptive immune responses, based on immunological approaches around acne initiation, has been achieved. Important next steps will be to investigate the molecular mechanisms for particular P. acnes phylotypes that stimulate the innate immune response within the local microenvironments that arise during the initial phase of acne lesion development. Additionally, it will be important to examine the respective roles of IL‐1 in this process. The possible contributions of Th17 cells to acne pathogenesis are also novel and interesting, but more studies are needed to investigate the interaction of the in vitro effects of P. acnes on IL‐17 expression with the progression of acne inflammation over time. Moreover, the clinical relevance of these findings must be established before any novel treatments can be considered.

Secondly, future studies are likely to reveal more intimate associations between the four ‘distinct’ pathogenic processes in detail. Recent results have demonstrated that these conventional factors are surprisingly closely interrelated with each other, much more in fact than previously expected (Fig. 1). As described above, both initiation and amplification of inflammation are closely associated with both P. acnes strain diversity and infundibular hyperkeratinization at the molecular and cellular levels.29, 30, 51, 69, 70 The lipogenesis pathway, which was thought to be independent, is also strongly affected by inflammatory cytokines and possibly by P. acnes itself.40, 71 Consequently, we strongly believe that the degree of contribution of one specific factor to acne physiopathology largely depends on the status of the other factors. Therefore, future research should consider acne pathogenesis in integrative and comprehensive ways to elucidate a clearer picture of the process.

Figure 1 Open in figure viewer PowerPoint New insights into the interconnectivity of the four major pathogenic factors of acne. IL, interleukin; P. acnes, Propionibacterium acnes; Th, T helper cell; TLR, Toll‐like receptor.

Thirdly, detailed elucidation of acne physiopathology at the molecular level would prompt future development of targeted medications. A thorough understanding of the sophisticated interactions of the inflammasome and Th17 cells, allowing specific targets to be pinpointed, would provide a novel target for therapy, which might ultimately prevent painful inflammatory lesions and subsequent scarring. In addition to biologics, the development of new low‐molecular‐weight drugs that antagonize target proteins that are known to accelerate lipogenesis and hyperproliferation of sebocytes would be expected to lead to new treatment options, not only for acne but also for seborrhoea.

Finally, several factors, including diet and genetic factors, have been largely neglected in acne physiopathology research. However, recent well‐designed clinical studies have demonstrated causal relationships between acne and nutrition, and researchers have provided constructive views to support this relationship at the molecular level.55-63 It is to be hoped that recent genome‐wide linkage and association studies might reveal hidden culprit genes involved in acne physiopathology that might explain a hereditary susceptibility to acne and acne scarring.64, 65 Validating the hypothesis that there could be genetic factors underpinning acne physiopathology could provide valuable information for the development of new medications, thus research should be conducted at both the macroscopic and microscopic levels.

In conclusion, we have reviewed some of the latest findings concerning the physiopathology of acne. The accumulation of information from these efforts will surely be helpful in providing a more detailed, integrated view of the whole spectrum of this most prevalent skin disease. Moreover, this work should lead to the development of novel therapeutics for acne and remnant scarring on the face, ultimately liberating patients from physical and psychosocial morbidities.