Acne: Transient Arrest in the Homeostatic Host–Microbiota Dialog?
Authors: Andrea Szegedi, Zsolt Dajnoki, Tamás Bíró, Lajos Kemény, Dániel Törőcsik
Journal: Trends in Immunology (2019)

We propose that acne vulgaris represents a naturally developing, transient inflammatory interaction of adolescent facial skin with its new microbial/chemical milieu (Cutibacterium acnes, sebum), replacing a state of previous childhood skin homeostasis. This concept might explain why acne is characterized by strong regional and age specificity, prevalent occurrence, and resolution. We propose that acne vulgaris represents a naturally developing, transient inflammatory interaction of adolescent facial skin with its new microbial/chemical milieu (Cutibacterium acnes, sebum), replacing a state of previous childhood skin homeostasis. This concept might explain why acne is characterized by strong regional and age specificity, prevalent occurrence, and resolution. Inflammatory skin diseases (ISDs) are common, noncommunicable dermatoses that can diminish a patient's quality of life. Most ISDs affect specific skin regions, similar to the joint preference of rheumatic diseases [1Ospelt C. Frank-Bertoncelj M. Why location matters – site-specific factors in rheumatic diseases.Nat. Rev. Rheumatol. 2017; 13: 433-442Crossref PubMed Scopus (24) Google Scholar]. Among ISDs, acne vulgaris can be considered a unique entity, due to the specific localization on sebaceous-gland-rich (SGR) skin regions and manifestation within a narrow age range associated with puberty [2Moradi Tuchayi S. et al.Acne vulgaris.Nat. Rev. Dis. Primers. 2015; 115029Crossref PubMed Scopus (46) Google Scholar]. Acne vulgaris occurs in 44–95% of teenagers of varying ethnicities, in contrast to the much lower frequency of other ISDs (e.g., psoriasis 2% and rosacea 2–10%) [2Moradi Tuchayi S. et al.Acne vulgaris.Nat. Rev. Dis. Primers. 2015; 115029Crossref PubMed Scopus (46) Google Scholar]. Furthermore, spontaneous remission of acne vulgaris occurs in up to 50% of affected patients, in contrast to other ISDs (e.g., psoriasis and rosacea), which have chronic intermittent courses [2Moradi Tuchayi S. et al.Acne vulgaris.Nat. Rev. Dis. Primers. 2015; 115029Crossref PubMed Scopus (46) Google Scholar]. To our knowledge, no ISDs, besides acne vulgaris, are characterized by both region and age specificity and such a high prevalence followed by frequent resolution. Thus, we posit that acne vulgaris might represent an individual ISD group. In light of new immunological and dermatological data, we propose a new concept for acne vulgaris pathogenesis, which might facilitate a better understanding of this disease leading to improved treatments. To simplify our hypothesis, we exclusively discuss teenage acne vulgaris (age 13–19 years). All our barrier surfaces are inhabited by commensal microbes. The interactions between epithelial barriers and the microbiota are variable, within a spectrum ranging from mutualism to pure pathogenicity [3Byrd A.L. et al.The human skin microbiome. Nat.Rev. Microbiol. 2018; 16: 143-155Google Scholar] (Table S1 in the supplemental information online). Initial colonization of our skin commences immediately after birth and the microbial communities become stabilized in the first years of life [4Oh J. et al.Shifts in human skin and nares microbiota of healthy children and adults.Genome Med. 2012; 4: 77Crossref PubMed Scopus (190) Google Scholar]. During this period, the skin immune system (SIS) evolves closely with microbes. This coevolution is essential for the education of the SIS, and the SIS can tolerate changes in microbiota populations during this time. In neonatal murine skin, this early tolerogenic period is mediated by the appearance of regulatory T (Treg) cells (see Glossary), as measured by flow cytometry [5Scharschmidt T.C. et al.A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes.Immunity. 2015; 43: 1011-1021Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar]. Then, a homeostatic dialog between the microbiota and the developed SIS evolves – characteristic of most later periods of human life (childhood and adulthood). Controlled production of complement system components, antimicrobial peptides (AMPs), and interleukin (IL)-1 from keratinocytes and dendritic cells (DCs) are considered as important innate mediators of this symbiotic relationship [3Byrd A.L. et al.The human skin microbiome. Nat.Rev. Microbiol. 2018; 16: 143-155Google Scholar]. Hair follicles can be recognized as special niches during this crosstalk, as they can preserve the steady-state by supporting the residency and recruitment of Langerhans cells, Treg cells, and by the reliance on innate lymphoid cells [6Kobayashi T. et al.Homeostatic control of sebaceous glands by innate lymphoid cells regulates commensal bacteria equilibrium.Cell. 2019; 176: 982-997.e16Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar]. Follicles, covered by a thin epithelial layer compared to cornified multilayered interfollicular epithelium, can be considered as locus minoris resistentiae of the skin, which may explain its pivotal role in the host–microbe dialog. This homeostatic crosstalk may be impaired upon changes of the dialog partners. During puberty, increased concentrations of androgenic hormones enhance sebaceous gland proliferation and sebum production. The greatest density of enlarged glands, and most sebum production, are found on the face, scalp, and upper back (SGR skin); therefore, a lipid-rich environment and a consequent shift in the skin microbiota occur in this area [4Oh J. et al.Shifts in human skin and nares microbiota of healthy children and adults.Genome Med. 2012; 4: 77Crossref PubMed Scopus (190) Google Scholar, 7Thiboutot D. Regulation of human sebaceous glands.J. Invest. Dermatol. 2004; 123: 1-12Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. The new microbiota of SGR skin is characterized by an increased relative abundance of lipophilic Cutibacterium (e.g., Cutibacterium acnes) and Corynebacterium (e.g., Corynebacterium simulans) compared to childhood [4Oh J. et al.Shifts in human skin and nares microbiota of healthy children and adults.Genome Med. 2012; 4: 77Crossref PubMed Scopus (190) Google Scholar]. As shown in a murine model, even a short-term encounter with a new commensal on the skin can initiate a robust accumulation of effector T cells producing IL-17 and interferon (IFN)-γ as well [8Naik S. et al.Commensal-dendritic-cell interaction specifies a unique protective skin immune signature.Nature. 2015; 520: 104-108Crossref PubMed Scopus (408) Google Scholar]. Based on these data, we hypothesize that the sudden permanent changes in the microbiota composition of SGR skin during adolescence, which accompany increased sebum with its own inflammatory potential, may result in an inflammatory response, bypassing previous host–microbiota homeostatic crosstalk, and leading to acne manifestation. During this event, secretion of homeostatic mediators may increase in the skin, with keratinocytes and DCs producing increased concentrations of proinflammatory cytokines; this could lead to keratinocyte proliferation, the activation of T helper (Th)17 and Th1 cells, and the influx of neutrophils and macrophages. This shift from a homeostatic to an inflammatory state, could be initiated in follicles, resulting in follicular hyperkeratinization, closure of the follicular infundibulum, and comedone formation; these would be the first visible signs of acne, followed later by the appearance of papules, pustules, and nodules (Figure 1). This hypothesis is supported by mRNA data demonstrating that cytokines that are also characteristic of homeostatic host–microbiota dialog (transcripts encoding IL-1α and β, IL-10, AMPs, and IL-17) are increased in acne lesions, and promote inflammation together with newly produced inflammatory mediators [IL-6, IL-12, IL-23, tumor necrosis factor (TNF)-α, IFN-γ], relative to healthy skin [9Kelhala H.L. et al.IL-17/Th17 pathway is activated in acne lesions.PLoS One. 2014; 9e105238Crossref PubMed Scopus (82) Google Scholar]. Furthermore, C. acnes is capable of inducing both homeostatic and inflammatory states in vitro. In response to C. acnes, human keratinocytes, sebocytes, and mononuclear cells produce IL-1β, IL-10, AMPs, IL-17, IL-6, IL-12, TNF-α, and IFN-γ [10Thiboutot D.M. et al.IL-17: a key player in the P. acnes inflammatory cascade?.J. Invest. Dermatol. 2014; 134: 307-310Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. Further work using fluorescent microscopy confirmed that acne development was associated with the presence of C. acnes and its biofilm formation in skin samples from human subjects, while disease severity correlated with C. acnes lipase activity in acne lesions [11Higaki S. et al.Correlation between Propionibacterium acnes biotypes, lipase activity and rash degree in acne patients.J. Dermatol. 2000; 27: 519-522Crossref PubMed Scopus (40) Google Scholar, 12Jahns A.C. et al.An increased incidence of Propionibacterium acnes biofilms in acne vulgaris: a case-control study.Br. J. Dermatol. 2012; 167: 50-58Crossref PubMed Scopus (139) Google Scholar]. Moreover, C. acnes is characterized by high phenotypic variability and C. acnes strains associated with acne (e.g., HL110PA1 and HL096PA1) are capable of inducing inflammatory IL-17/IL-IFN-γ-producing CD4+ T cells; by contrast, other C. acnes strains associated with healthy skin (e.g., HL042PA3 and HL110PA4) promoted protective IL-17/IL-10-producing Th cell phenotypes, as evidenced from flow cytometry and ELISA data [13Agak G.W. et al.Phenotype and antimicrobial activity of Th17 cells induced by Propionibacterium acnes strains associated with healthy and acne skin.J. Invest. Dermatol. 2018; 138: 316-324Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. The presence of high sebum production in teenagers seems to be essential for the otherwise commensal C. acnes community to exert its capacity of initiating inflammation. The highest secretion rate of sebum occurs during adolescence, declining even in post-adolescence and throughout [7Thiboutot D. Regulation of human sebaceous glands.J. Invest. Dermatol. 2004; 123: 1-12Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. Moreover, the sebum composition is altered in acne, and sebum concentrations correlate with disease severity [2Moradi Tuchayi S. et al.Acne vulgaris.Nat. Rev. Dis. Primers. 2015; 115029Crossref PubMed Scopus (46) Google Scholar]. Sebum can potentiate the propagation of C. acnes strains and can induce inflammation and follicular hyperkeratinization [2Moradi Tuchayi S. et al.Acne vulgaris.Nat. Rev. Dis. Primers. 2015; 115029Crossref PubMed Scopus (46) Google Scholar]. Indeed, others have referred to sebum as the 'fuel of the acne flame'. Thus, we posit that sebum might play a predominant role in driving the shift from homeostasis to inflammation. In the presence of C. acnes, human macrophages treated in vitro with different sebum components (e.g., palmitic and oleic acid) secrete significantly elevated concentrations of IL-1β and TNF-α, relative to controls, as shown by ELISA [14Lovaszi M. et al.Sebum lipids influence macrophage polarization and activation.Br. J. Dermatol. 2017; 177: 1671-1682Crossref PubMed Scopus (32) Google Scholar]. Hence, the extent or quality of the interactions between C. acnes and SGR skin may be modulated by sebum. We posit that acne is a naturally occurring transient arrest of a homeostatic host–microbe dialog on SGR skin during adolescence. Part of our hypothesis is that the SIS tries to re-establish homeostasis again in post-adolescence, recognizing (tolerizing) the renewed microbial/sebum milieu as harmless. This might lead to the spontaneous resolution of acne. Multiple events (reduced sebum, compositional changes in C. acnes strains, regulation of SIS, and improved barrier integrity, among others) could influence the time of acne resolution, but this needs to be robustly assessed. Genome-wide association data, primarily in adolescents and young adults with severe acne relative to controls, indicate that polymorphisms in inflammatory genes (e.g., TNFA, IL1A, and IL6), and also genes playing a role in the initiation of tolerance (DBB2, TGFB2, OVOL1, SELL, TP63, and FST), have been associated with disease manifestation [15Lichtenberger R. et al.Genetic architecture of acne vulgaris.J. Eur. Acad. Dermatol. Venereol. 2017; 31: 1978-1990Crossref PubMed Scopus (25) Google Scholar]. Moreover, immunohistochemistry has revealed increased numbers of noninflammatory Th17 cells, nonactivated DCs, and Treg cells, along with thymic stromal lymphopoietin (TSLP) expression, and a IL-17/IL-10-positive cytokine milieu in adult SGR skin, compared to other skin regions (e.g., sebaceous gland poor) [16Dajnoki Z. et al.Sebaceous gland-rich skin is characterized by TSLP expression and distinct immune surveillance which is disturbed in rosacea.J. Invest. Dermatol. 2017; 137: 1114-1125Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. These unique features of SGR regions might potentially represent remnants of previous inflammation and acne, and a subsequent inflammatory resolution [16Dajnoki Z. et al.Sebaceous gland-rich skin is characterized by TSLP expression and distinct immune surveillance which is disturbed in rosacea.J. Invest. Dermatol. 2017; 137: 1114-1125Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar] (Figure 1). In summary, we propose that the development of acne vulgaris is driven by dynamic changes in the interactions between adolescent SGR skin and its microbial/chemical milieu relative to childhood. This, in turn, might lead to a state of transient inflammation, rather than homeostasis. Presumably, this transition might be accepted as part of the physiological maturation of our SIS: a transient arrest in homeostasis (see Table S2 in the supplemental information online). From a clinical perspective, although immune-mediated inflammation in acne is viewed as physiological, there is a high risk of permanent scar and pigment formation. Hence, patients may require specific treatments. Moreover, the mechanisms that initiate, amplify, resolve, or perpetuate acne might have common pathways with other organ systems, and the knowledge gained on a broader scale on this front might inform the potential development of improved treatments in acne. This publication is supported by Hungarian Research Grant ( NKFIH K-128250 ), the GINOP-2.3.2-15-2016-00050, and EFOP-3.6.1-16-2016-00022 projects. The project is co-financed by the European Union and the European Regional Development Fund and the European Social Fund . DZS and TD are recipients of the János Bolyai research scholarship of the Hungarian Academy of Sciences and TD was also supported by the UNKP-18-4 New National Excellence Program of the Ministry of Human Capacities . Download .docx (.02 MB) Help with docx files Supplementary Material dilated infundibulum plugged by lipids and keratin. When the infundibulum is open to the skin surface, the lesion is called open comedone (black color is due to the oxidized sebaceous content). A closed infundibulum accumulating whitish keratin is referred to as a closed comedone. upper part of the hair follicle that begins at the epidermal surface and extends to the opening of the sebaceous gland duct. immune cells that belong to the lymphoid lineage, defined by the absence of antigen specific B or T cell receptor; they have important functions in innate immunity against infectious microorganisms as well as in regulating inflammation and homeostasis. dendritic antigen-processing and -presenting cells localized in the skin epidermis. 'place of lesser resistance'. It refers to a body region that is more vulnerable than others, offering little resistance to microorganisms. (in skin): a solid, ellipsoidal, palpable lesion with a diameter >0.5 cm. solid, elevated lesion <0.5 cm in size rising above the surrounding skin surface. circumscribed, projecting, pus-containing cavity in the infundibulum. Foxp3-expressing subset of CD4+ T cells; modulators of immunity, they maintain tolerance to self-antigens, and prevent autoimmune disease by potently downregulating or suppressing the induction and proliferation of effector T cells. subset of CD4+ T cells responsible for killing intracellular parasites and for perpetuating autoimmune responses. IFNγ is the main inflammatory cytokine produced by Th1 lymphocytes. multifaceted IL-17-secreting T cell lineage with high plasticity, with physiological or pathological roles in at least three different levels. In healthy skin, they maintain homeostasis by supporting the integrity of the skin barrier by controlling commensal bacteria, inducing tight junctions, and expressing antimicrobial proteins They also protect barriers against pathogenic extracellular microorganisms, They are key players in the initiation and maintenance of inflammatory and autoimmune diseases. Th17 cells can be arbitrarily divided into non-pathogenic Th17(β) and pathogenic Th17(23) subtypes.