Coming up with a protocol for treatment of acne requires understanding of acne mode of development. Although, the precise mechanisms of acne are not known, it is clearly accepted that there are four major factors involved in pathogenesis of acne :
1. An increased sebum production under androgen influence .
2. Ductal hypercornification (hyperproliferation of ductal epidermis) Hypercornification is overproduction of epithelial cells lining follicles (sebaceous ducts, these ducts conduct sebum to the skin). Hypercornification of pilosebaceous ducts can be seen histologically as microcomedones .
3. Bacterial colonization of the duct with Propionibacterium acnes.
4. Further production of inflammation in acne sites, perifollicular inflammation  .
Acne and sebum production: Several factors influence sebum production, but it is predominantly hormonally stimulated which guides hormonal therapy in acne. Androgens especially from the testes and adrenals, stimulate the sebaceous gland directly and influence acne inflammation. Sebacous glands are recognized as an endocrine organ as seobocytes possess androgen nuclear receptors, implicated in sebocyte differentiation and apoptosis.
Diacylglycerdies have been found to be increased in acne vulgaris whether as a direct result of triglycerides catabolism or their defective anabolism under influence of propriobacterium.acnes.
In addition, the skin and its appendages , including hair follicles and sebaceous glands are armed with all the necessary enzymes required for androgen synthesis . Two major enzymes work to produce androgens are 5-alpha reductase  and steroid sulfatase . In contrast, aromatase inactivate the excess androgens locally in order to achieve androgen homeostasis . In the skin the activity of the type1 5-alpha-reductase is concentrated in sebaceous glands and is significantly higher in sebaceous glands from the face and scalp compared with non-acne-prone areas . Estrogens exert a variable inhibitory effect in pharmacological doses.
Specific enzyme expression and activation in cultured seboyctes and keratinocytes seem to allocate different duties to these cells in vitro. Sebocytes are able to synthesize testosterone from adrenal precursors and to inactivate it in order to main androgen homeostasis, whereas keratinocytes are responsible for androgen degradation .
Peroxisome proliferator activated receptors, PPAR, are categorized as nuclear hormone receptors which form a dimer with retinoid X receptor and function in transcriptional regulation of genes involved in lipid metabolism in the skin, liver and adipose tissue. However, androgens in vitro have shown no similar effects (androgen synthesis). This suggests a role for cofactors such as PPAR ligands such as linoleic acid. Catalytic effect of PPAR (peroxisome proliferator-activated receptor) ligands were shown on cellular testosterone activation by which can regulate sebaceous lipids . PPAR ligands such as Zileuton or rosiglitazones induce lipogenesis and increase sebum production .
The sebaceous glands ( part of sebaceous follicles ) are under endocrine control and so it is not surprising that sebum production shows change according to age and sex of an acne patient. Sebum production is dramatically greater than that in females in normal individuals as well as acne patients. There is an increase in sebum production with a peak at about age 40. Any approach to control androgens appear to be relevant to adult acne since the sebaceous follicle ( sebaceous glands are located in the dermis, the middle layer of skin, secrete oil onto the skin and their overfunction may cause increase in skin’s oil production) is an organ targeted by androgens.
Hyper proliferation of ductal epidermis, histologically seen as microcomedones, is associated with development of adult acne. there is a significant correlation between the severity of acne and number and size of microcomedones . A possible stimulus to pilosebaceous duct hypercornification could be hormones, in particular androgens . Androgens exert their effect through dihydrotestosterone (DHT), which is primarily responsible for androgen receptor binding and exerting end-organ effects . In sebaceous glands, androgen receptors are identified in basal and differentiation sebocytes . Overall levels of 5-alpha-reductase, converting testosterone to DHT, have been shown to be higher in the sebaceous glands of patients with acne than those without acne .
From the other hand, within the duct, variations in the lipid composition have been put forward to explain comedones ( a initial acne lesion ) formation, which could be either closed (whiteheads, see photo) or open (blackheads). Sebum analysis indicates variations which include an increased concentration of squalene, squalene oxide, and certain fatty acids. This change in qualitative change in sebum lipids induce alteration of kertinocyte differntiation and induce IL-1 secretion, contributing to the development of follicular hyperkeratosis .
A decrease in the linloleic acid fraction of the skin surface lipids has been shown in a patient with acne. Hints that omega-3 fatty acids might positively influence acne originate from older epidemiological studies which show that communities that maintain a traditional diet high in omega-3 fatty acids have low rates of acne .
Skin surfaces in the acne prone areas are colonized with Staphylococcus epidermidis and Propionibacterium acnes, which plays a critical role in development of acne . Several mechanisms may explain role of p.acnes in development of acne . One mechanism seems to be direct effect of p.acnes on keratinocytes through interaction with toll like receptors TLR-2 and TLR-4, which leads to release of inflammatory cytokines such as IL-1alpha and beta, IL-8, GM-CSF and TNF-alpha  . Studies suggest that bacteria have nothing to do with the initiation of comedogenesis. However, P. acnes, in particular, may in some situations be important in the initiation of inflammation. It is also quite likely that they are involved in a perpetuation of inflammation once established.
The adult acne inflammation is not, in most cases, an abnormal response of the immune system. The inflammation represents a normal immune and non-immune response to foreign substances penetrating the dermis. Keratinocytes express anti-microbial peptides constitutively and upon injury or infection, e.g. by stimulation of TLRs (toll like receptors) through PAMPs and DAMPs . However, the skin can also be a site of excessive immune responses as part of the innate immune response . Therefore, on the one hand the skin must ensure an efficient defense against pathogens and on the other hand the skin must minimize excessive immune responses which can result in disease states.
Keratinocytes play an important role in the inflammatory reaction of the skin, synthesizing a number of cytokines, adhesion molecules and growth factors which in one way or another affect sebum production . Sebaceous glands and sebocytes in culture were shown to produce IL-1alpha . in The cytokines that proved essential at the onset of inflammation and during an innate immune response include proinflammatory cytokine interleukin-1 (IL-1) . Keratinocytes essentially express inflammasone proteins as well as proIL-1alpha and beta, which can be transformed to active forms by certain conditions such as UV irradiation , associated with increase in sebum synthesis and acne aggravation.
Interactions between IL-1, sebaceous hyperproliferation and P.acnes. Comedo formation is associated with increase in IL-1alpha and becomes more inflammatory with colonization of P.acnes. Inflammation could be initiated through mediation of CD4+ T-cells or by a more nonspecific mechanism through involvement of cytokines such as TNF-alpha. .
Study by Yosipovitch et al, cast doubt on existence of a direct link between stress and quantitative sebum levels, however, a positive correlation was found between stress experienced by male patients and severity of acne lesions, which may be attributed to alteration in sebum composition rather than its produced amount as well as neuropeptide secretion, suggestively CRH.
Addition of DHT to cultured sebocytes has been demonstrated to increase immunoreactity of IL-6 and TNF-alpha .
TNF-alpha induces lipogenesis in SZ95 human sebocytes through the JNK (c-Jun N-terminal Kinase) and phosphoinositide-3-kinase pathways .
Patients with severe acne such as cysts have been benefited by a treatment with anti-inflammatory agents . Enzymes involved in the biosynthesis of the proinflammatory lipids leukotriene LTB4 and prostaglandin-E2 are activated in sebceous gland of acne lesions . LTB4 is now known to up regulate sebm production and synthetic inhibition of LTB3 in the form of drug zileuton leads to significant improvement in acne . Fish oil EPA (eicosapentaenoic acid) and GLA (gamma-linolenic acid) have been reported to inhibit the conversion of arachidonic acid into LTB4 to the same degree as the LTB4-inhibiting acne drug candidate zileuton .
Polyphenols have been suggested to down-regulate sebaceous gland metabolism and attenuate increase in sebum synthesis associated with acne. UVA, visible light and infrared have been found to be effective in control of sebaceous lipids and their contribution in pathogenesis of acne vulgaris, without invoking epithelial inflammatory response.
Skin seems to be equipped with necessary enzymes involved in androgen synthesis. 5-alpha-reductase, steroid sulfatase, HSD1 (hydroxysteroid dehydrogenase) and HSD3 are all available at sebaceous glands level. Aromatase also involves at the skin level to maintain homeostasis .
Among non-steroidal inhibitors of 5-alpha-reductase, zinc, isoflavanoids, gamma-linolenic acid could be names. Genistein, thiozolidinediones are examples of non-steroidal inhibitors of HSD3 .
Androgens may be the initial trigger of a change in the skin that may lead to comedone/acne formation. Androgens implement their effect by eliciting an inflammatory response and by increasing lipogenesis concurrent with change in skin lipid composition at sebocytes. This change in skin surface lipid composition exacerbates inflammatory response and provides an environment more prone for P.acnes colonization.
P.acnes itself is responsible for exaggerating inflammatory response by inducing an acute, transient transcriptional inflammatory response in keratinococytes, suggested by a comparative global-transcriptional analyses for P.acnes infection of keratinocytes . P.acnes contributes to the inflammatory nature of acne by inducing monocytes to secrete proinflammatory cytokines including TNF-alpha, IL-1Beta and IL-8 . P.acnes triggers inflammatory cytokine responses in acne by activation of TLR2, which may be a target for treatment .
Onset of sebum synthesis in sebaceous glands and consequently expansion of the propionibacterial skin flora occur earlier in children who develop acne than in children of the same age and pubertal status who do not develop acne . This study does not explain if this phenomenon is independent of androgens and if this occurrence should be counted as role of genetics factors as predisposing to this event.
It seems that there’s a fluctuating dialogue among various factors that in one way or another contribute to acne/comedone development. Alteration in androgen levels, change in lipidogenesis qualitatively and quantitatively, inflammatory response, keratinocyte proliferation, bacterial colonization and lipid peroxidation by free radicals. This ever present interactions among these factors fluctuates course of acne vulgaris, which, seemingly, demand a treatment targeting all elements of this interactive cycle.
Progression of TLR-2 expression in acne according to the evolution of the lesion. After 6 hours only a few TLR2 positive cells were detected. However, the number of TLR2 positive cells continue to increase with time .
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