The prerequisite for the development of acne is hyperkeratosis of the sebaceous ducts of the hair follicles. Alterations in sebum composition, the action of local androgens, and the secretion of inflammatory factors due to Propionibacterium acnes all have a role in promoting hyperkeratosis. A review of the research progress in this area is presented.
Acne is the most basic pathological change of acne. The initial manifestation of acne formation is hyperkeratosis of the follicular sebaceous ducts. What factors contribute to hyperkeratosis of the follicular sebaceous ducts? The detailed mechanism is not clear, but several factors are involved.
I. Formation of hyperkeratosis of follicular sebaceous ducts
Hyperkeratosis of the follicular sebaceous ducts is caused by hyperproliferation of the ductal keratin-forming cells and reduced shedding of the endothelial keratinized cells. Ductal cell hyperproliferation has been supported experimentally by immunohistochemical studies using Ki67, a marker antibody for cell proliferation, which revealed significantly stronger staining of the epithelial basal cells of hair follicles in acne than in hair follicles not invaded by acne. Keratin 16 is a marker of abnormal differentiation and overproliferation of keratin-forming cells, and expression of keratin 16 by keratin-forming cells in the sebaceous ducts of acne follicles indicates hyperkeratinization of the epithelium and abnormal cell proliferation [1]. The keratinized keratin-forming cells in acne follicles become dense with increased intercellular adhesion and are not easily detached. Hyperproliferation of catheter keratin-forming cells and impaired desquamation of the endothelium lead to the formation of keratinocytes and obstruction of the follicular canal, thus inducing the formation of acne.
Second, changes in cellular junction components lead to disorders of desquamation
Electron microscopic studies revealed a large increase in tension microfilaments and bridging grains in acne follicle epithelial cells. However, no difference in the antigenic composition of bridging granules was observed when comparing between acne-invaded and non-invaded hair follicles. Bridging granules are intercellular connections and intracellular pericytes may be involved in desquamation, thus increased intercellular bridging granules increase intercellular connections and decreased intracellular pericytes lead to impaired desquamation [2]. The presence of a glycoprotein in the cell matrix called cytoadhesive protein, which can interact with cells to alter cell adhesion, migration and proliferation, has been shown to increase the expression of adhesive in the sebaceous ducts of acne follicles, which may also affect cell adhesion [3].
In a model of rabbit ears, topical application of oleic acid can lead to acne formation, and histological observations showed that the epithelium of the follicular ducts appeared multilayered and tightly keratinized after oleic acid treatment, the number and size of hyaline keratin granules increased, and the keratinized cells were tightly bound together by bridge grains. desquamation [4]. Thus, the main ultrastructural changes in acne formation are the increase in intercellular bridging grains and the decrease in intracellular Odland vesicles, both of which contribute to the disorder of desquamation.
Third, changes in lipid composition and hyperkeratosis of follicular sebaceous ducts
Acne lesions contain a large number of Propionibacterium acnes, which can generate enzymes that break down sebum, thus leading to changes in sebum composition. For example, triglycerides can be broken down to produce glycerol and free fatty acids, which are the main source of free fatty acids in sebum, but recent studies have shown that sebaceous gland cells themselves can produce small amounts of free fatty acids. In acne patients, free fatty acid production is increased in the lesions. Kligman first found that free fatty acids can cause increased keratinization of follicular ducts, and in animal models, exogenous free fatty acids can induce acne production. Squalene and squalene peroxide in the sebum component are produced by the metabolism of sebum by Propionibacterium acnes. Squalene has a mild pro-comedogenic effect, but the peroxide of squalene has a strong pro-comedogenic effect, and the main mechanism of action of squalene and squalene peroxide is the induction of hyperkeratosis of the epithelium of the follicular sebaceous ducts [5].
In acne patients with lower than normal levels of linoleic acid in the skin, it may be associated with hyperkeratosis of the ducts [6]. Linoleic acid is a polyunsaturated fatty acid, and its lack in food can cause scaly dermatoses. Topical application of linoleic acid can dissolve acne and shrink it.
The role of androgens in hyperkeratosis of hair follicle sebaceous ducts
Androgens mainly increase the activity of sebaceous glands in the pathogenesis of acne, but some studies have shown that androgens play an important role in controlling hyperkeratosis of the follicular sebaceous ducts, The keratin-forming cells in the funiculus have a stronger ability to metabolize androgens, which may be related to the hyperkeratosis of the funiculus [7]. In a rabbit ear model, exogenous local injection of androgens induced hyperkeratosis of the hair follicle ducts.
V. Role of microorganisms and inflammatory factors in promoting the keratinization of follicular sebaceous gland ducts
In the follicular sebaceous gland unit, especially on the basis of microcomedema formation, sebum can provide a good culture medium and anaerobic conditions for Propionibacterium acnes, which can proliferate and cause disease. The main role of P. acnes in the pathogenesis of acne is the induction of the body’s immune response and the development of local inflammation, but it is also involved in the hyperkeratosis of the follicular duct epithelium [8]. The main component of newly generated sebum is triglyceride with a certain amount of wax lipids, squalene and a small amount of cholesterol and cholesterol lipids, however, after secretion into the ducts, its composition is changed due to the secretion of lipase by bacteria, which increases free fatty acids, 95% of which are generated by the action of lipase produced by Propionibacterium acnes, along with squalene and squalene peroxide. The keratinization of follicular ducts is indirectly promoted by the abnormal microorganisms that cause lipids.
VI. Retinoic acid and follicular keratinization
Vitamin A and its active form retinoids are essential in maintaining epidermal cell differentiation. Retinoids affect cell proliferation and differentiation, regulate immune responses, regulate DNA synthesis and thus protein expression, inhibit sebum production and have anti-inflammatory effects. The mechanism of action of retinoids depends on the tissue on which it acts. In epidermal keratin-forming cells, the nucleus has receptors for retinoids, which belong to the steroid receptor family. Retinol is converted to retinoic acid, i.e. retinoic acid, which binds to CRABP in the cytoplasm and enters the nucleus through the transport of retinoic acid by CRABP, where it binds to retinoic acid receptors (RARS) to form a complex. It is not known whether the receptor for cis-retinoic acid is the same as the retinoic acid receptor. In the nucleus, the retinoic acid complex acts as a transcription factor regulating the expression of genes and thus the activity of the epidermis [15]. Deficiency of natural retinoic acid can cause abnormal differentiation of sebaceous gland cells and hyperkeratosis of hair follicle ducts.CRABP can control the concentration of retinoic acid in epidermal keratin-forming cells, thus indirectly regulating gene expression.
In cultured human keratin-forming cells, retinoic acid induced ultrastructural changes and inhibited cell proliferation. In animal model studies, retinoic acid was found to reduce keratinization of follicular ducts and to have a solubilizing effect on acne. It has the same effect in cultured human follicular sebaceous gland units [16]. Clinically, retinoic acid has been found to be effective for acne either topically or orally. This suggests that abnormalities in retinoic acid can affect the keratinization of follicular ducts.
VII. Genetic control of hyperkeratosis of follicular ducts
Since the rate of sebum production is related to follicular keratinization, genetic factors control follicular keratinization by controlling sebum production. A mutation in the front end of the murine X chromosome, expressed as a broken fragment, can occur, and this mutation is associated with prenatal mortality in males. This corresponding fragment has also been found in humans. Histological analysis of skin taken from the dorsum of heterozygous rats with this mutation 5 days postnatally showed that the mutation in the gene resulted in hyperkeratosis of the epithelium and hair follicles along with subcutaneous infiltration of inflammatory cells [17].
Vitamin A, endogenous retinoic acid and their metabolites can affect sebaceous gland morphology and keratinization of hair follicle sebaceous ducts, and cytochrome P450IAI (CYPIAI) is the most active of the three reciprocal mutations, and CYPIAI can have multiple isoenzymes expressed by different genes with widely varying efficacy. A study of polymorphisms in CYPIAI genes in acne patients revealed that the M1-type allele is highly expressed in acne patients. M1-type regulates changes in the regulatory site of the enzyme, due to which natural retinoic acid is rapidly metabolized into inactive complexes, resulting in a significant reduction in the biological activity of natural retinoic acid. The result of natural active retinoic acid deficiency causes abnormal differentiation of sebaceous gland cells and hyperkeratosis of hair follicle ducts [18]. Thus, genetic factors control the metabolism of retinoic acid and thus regulate the keratinization of the follicular sebaceous ducts.
Conclusion
Hyperkeratosis of the follicular sebaceous ducts is the result of a combination of factors, almost all of which are involved in the development of acne, and duct keratinization is the basis for the development of acne on which other lesions occur. However, there are still many unanswered questions about hyperkeratosis of the follicular sebaceous ducts, such as why does hyperkeratosis of the follicular sebaceous ducts occur only after puberty? What is the exact mechanism of action of androgens in hyperkeratosis of follicular sebaceous ducts? What are the characteristics of the distribution of all cytokines in hyperkeratosis of the follicular sebaceous ducts and what is the mechanism of action between them? The solution to these questions will help to elucidate the pathogenesis of acne and find more effective treatments for acne.