Editing Acne (section)

==Pathophysiology==
[[File:Comedo.png|thumb|upright=1.3|Simplistic representation of the formation of acne comedones]]
[[File:Blausen 0811 SkinPores.png|thumb|upright=1.3|Hair follicle anatomy demonstrating a healthy hair follicle (pictured left), a whitehead or closed comedo (middle picture), and a blackhead or open comedo (pictured right)|alt=Three images illustrating hair follicle anatomy]]
[[File:Acne Pathogenesis Medscape.png|thumb|upright=1.3|Flowchart of the pathological sequence of events leading to acne|alt=Image illustrating a flowchart of the pathophysiology of acne]]

Acne vulgaris is a chronic skin disease of the [[pilosebaceous unit]] and develops due to blockages in the skin's [[hair follicle]]s.<ref name=Simonart2013/>

Traditionally seen as a disease of adolescence, acne vulgaris is also observed in adults, including post-menopausal women. Acne vulgaris manifested in adult female is called ''adult female acne'' (AFA), defined as a chronic inflammatory disease of the pilosebaceous unit.<ref name="pmid38650835">{{cite journal |vauthors=Dias da Rocha MA, Saint Aroman M, Mengeaud V, Carballido F, Doat G, Coutinho A, Bagatin E |title=Unveiling the Nuances of Adult Female Acne: A Comprehensive Exploration of Epidemiology, Treatment Modalities, Dermocosmetics, and the Menopausal Influence |journal=Int J Womens Health |volume=16 |pages=663–678 |date=2024 |pmid=38650835 |pmc=11034510 |doi=10.2147/IJWH.S431523|doi-access=free }}</ref> Particularly in AFA, during the menopausal transition, a relative increase in androgen levels occurs as estrogen levels begin to decline, so that this hormonal shift can manifest as acne; while most women with AFA exhibit few acne lesions and have normal androgen levels, baseline investigations, including an androgen testing panel, can help rule out associated comorbidities such as [[polycystic ovarian syndrome]], [[congenital adrenal hyperplasia]], or tumors.<ref name="pmid38650835"/>

The blockages in the skin's [[hair follicle]]s that cause acne vulgaris manifestations occur as a result of the following four abnormal processes: increased oily [[sebum]] production (influenced by [[androgen]]s), [[Hyperkeratinization|excessive deposition of the protein keratin]] leading to comedo formation, colonization of the follicle by ''Cutibacterium acnes'' (''C. acnes'') bacteria, and the local release of pro-inflammatory chemicals in the skin.<ref name=Simonart2013>{{cite journal | vauthors = Simonart T | title = Immunotherapy for acne vulgaris: current status and future directions | journal = American Journal of Clinical Dermatology | volume = 14 | issue = 6 | pages = 429–35 | date = December 2013 | pmid = 24019180 | doi = 10.1007/s40257-013-0042-8 | s2cid = 37750291 | type = Review }}</ref>

The earliest pathologic change is the formation of a plug (a [[Blackhead|microcomedone]]), which is driven primarily by excessive growth, reproduction, and accumulation of [[keratinocyte|skin cells]] in the hair follicle.<ref name=Vary2015/> In healthy skin, the skin cells that have died come up to the surface and exit the pore of the hair follicle.<ref name="Aslam2015"/> In people with acne, the increased production of oily sebum causes the dead skin cells to stick together.<ref name="Aslam2015"/> The accumulation of dead skin cell debris and oily sebum blocks the pore of the hair follicle, thus forming the microcomedone.<ref name="Aslam2015"/> The ''C. acnes'' [[biofilm]] within the hair follicle worsens this process.<ref name=Das2014/> If the microcomedone is superficial within the hair follicle, the skin pigment [[melanin]] is exposed to air, resulting in its [[oxidation]] and dark appearance (known as a blackhead or open comedo).<ref name=Vary2015/><ref name="Aslam2015"/><ref name=BMJ2013/> In contrast, if the microcomedone occurs deep within the hair follicle, this causes the formation of a whitehead (known as a closed comedo).<ref name=Vary2015/><ref name="Aslam2015"/>

The main hormonal driver of oily sebum production in the skin is [[dihydrotestosterone]].<ref name=Vary2015/> Another androgenic hormone responsible for increased sebaceous gland activity is [[Dehydroepiandrosterone|DHEA-S]]. The [[adrenal gland]]s secrete higher amounts of DHEA-S during [[adrenarche]] (a stage of [[puberty]]), and this leads to an increase in sebum production. In a sebum-rich skin environment, the naturally occurring and largely [[commensal]] skin bacterium ''C. acnes'' readily grows and can cause [[inflammation]] within and around the follicle due to activation of the [[innate immune system]].<ref name="Aslam2015"/> ''C. acnes'' triggers skin inflammation in acne by increasing the production of several pro-inflammatory [[cytokine|chemical signals]] (such as [[IL-1α]], [[Interleukin 8|IL-8]], [[TNF-α]], and LTB4); IL-1α is essential to comedo formation.<ref name=Das2014>{{cite journal | vauthors = Das S, Reynolds RV | title = Recent advances in acne pathogenesis: implications for therapy | journal = American Journal of Clinical Dermatology | volume = 15 | issue = 6 | pages = 479–88 | date = December 2014 | pmid = 25388823 | doi = 10.1007/s40257-014-0099-z | s2cid = 28243535 | type = Review }}</ref>

''C. acnes''' ability to bind and activate a class of [[immune system]] receptors known as [[toll-like receptor]]s (TLRs), especially [[toll-like receptor 2|TLR2]] and [[toll-like receptor 4|TLR4]], is a core mechanism of acne-related skin inflammation.<ref name=Das2014/><ref name=Andriessen2014>{{cite journal | vauthors = Andriessen A, Lynde CW | title = Antibiotic resistance: shifting the paradigm in topical acne treatment | journal = Journal of Drugs in Dermatology | volume = 13 | issue = 11 | pages = 1358–64 | date = November 2014 | pmid = 25607703 | type = Review }}</ref><ref name=Hammer2015>{{cite journal | vauthors = Hammer KA | title = Treatment of acne with tea tree oil (melaleuca) products: a review of efficacy, tolerability and potential modes of action | journal = International Journal of Antimicrobial Agents | volume = 45 | issue = 2 | pages = 106–10 | date = February 2015 | pmid = 25465857 | doi = 10.1016/j.ijantimicag.2014.10.011 | type = Review }}</ref> Activation of TLR2 and TLR4 by ''C. acnes'' leads to increased secretion of IL-1α, IL-8, and TNF-α.<ref name=Das2014/> The release of these inflammatory signals attracts various immune cells to the hair follicle, including [[neutrophil]]s, [[macrophage]]s, and [[Th1 cell]]s.<ref name=Das2014/> IL-1α stimulates increased skin cell activity and reproduction, which, in turn, fuels comedo development.<ref name=Das2014/> Furthermore, sebaceous gland cells produce more [[antimicrobial peptides]], such as [[Defensin, beta 1|HBD1]] and [[Beta-defensin 2|HBD2]], in response to the binding of TLR2 and TLR4.<ref name=Das2014/>

''C. acnes'' also provokes skin inflammation by altering the fatty composition of oily sebum.<ref name=Das2014/> Oxidation of the [[lipid]] [[squalene]] by ''C. acnes'' is of particular importance. Squalene oxidation activates [[NF-κB]] (a protein complex) and consequently increases IL-1α levels.<ref name=Das2014/> Additionally, squalene oxidation increases [[5-lipoxygenase]] enzyme activity, which catalyzes the conversion of [[arachidonic acid]] to [[leukotriene B4]] (LTB4).<ref name=Das2014/> LTB4 promotes skin inflammation by acting on the [[peroxisome proliferator-activated receptor alpha]] (PPARα) protein.<ref name=Das2014/> PPARα increases the activity of [[activator protein 1]] (AP-1) and NF-κB, thereby leading to the recruitment of inflammatory [[T cell]]s.<ref name=Das2014/> ''C. acnes''' ability to convert sebum [[triglyceride]]s to pro-inflammatory [[free fatty acid]]s via secretion of the enzyme [[lipase]] further explains its inflammatory properties.<ref name=Das2014/> These free fatty acids spur increased production of [[cathelicidin]], HBD1, and HBD2, thus leading to further inflammation.<ref name=Das2014/>

This inflammatory cascade typically leads to the formation of inflammatory acne lesions, including [[papule]]s, infected [[pustule]]s, or [[nodule (medicine)|nodules]].<ref name=Vary2015/> If the inflammatory reaction is severe, the follicle can break into the deeper layers of the dermis and [[subcutaneous tissue]] and cause the formation of deep nodules.<ref name=Vary2015/><ref name=Sieber2014>{{cite journal | vauthors = Sieber MA, Hegel JK | title = Azelaic acid: Properties and mode of action | journal = Skin Pharmacology and Physiology | volume = 27 Suppl 1 | issue = Supplement 1 | pages = 9–17 | date = November 2013 | pmid = 24280644 | doi = 10.1159/000354888 | s2cid = 8848543 | type = Review }}</ref><ref name=Simpson2004>{{cite book |last1=Simpson|first1=Nicholas B.|last2=Cunliffe|first2=William J. |year=2004 |chapter=Disorders of the sebaceous glands |pages=431–75|editor=Burns, Tony|editor2=Breathnach, Stephen |editor3=Cox, Neil |editor4=Griffiths, Christopher |title=Rook's textbook of dermatology |edition=7th |location=Malden, Mass. |publisher=Blackwell Science |isbn=978-0-632-06429-8}}</ref> The involvement of AP-1 in the aforementioned inflammatory cascade activates [[matrix metalloproteinase]]s, which contribute to local tissue destruction and scar formation.<ref name=Das2014/>

Along with the bacteria ''C. acnes'', the bacterial species ''Staphylococcus epidermidis'' (''S. epidermidis'') also takes a part in the physiopathology of acne vulgaris. The proliferation of ''S. epidermidis'' with ''C. acnes'' causes the formation of [[biofilms]], which blocks the hair follicles and pores, creating an [[wikt:anaerobic|anaerobic]] environment under the skin. This enables for increased growth of both ''C. acnes'' and ''S. epidermidis'' under the skin. The proliferation of ''C. acnes'' causes the formation of [[biofilms]] and a [[biofilm matrix]], making it even harder to treat the acne.<ref name=Claudel2019>{{cite journal | vauthors = Claudel V, Auffret N, Leccia MT, Poli F, Corvec S, Dréno B | title = ''Staphylococcus epidermidis'': A potential new player in the physiopathology of acne? | journal = Dermatology | volume = 235 | issue = 4 | pages = 287–94 | date = May 2019 | doi = 10.1159/000499858 | pmid = 31112983 | s2cid = 162170301 | type = Review | doi-access = free }}</ref>