Sebaceous immunobiology - skin homeostasis, pathophysiology, coordination of innate immunity and inflammatory response and disease associations

Christos C Zouboulis, Tom Coenye, Li He, Kenji Kabashima, Tetsuro Kobayashi, Catherin Niemann, Takashi Nomura, Attila Oláh, Mauro Picardo, Sven R Quist, Hironobu Sasano, Marlon R Schneider, Daniel Törőcsik, Sunny Y Wong, Christos C Zouboulis, Tom Coenye, Li He, Kenji Kabashima, Tetsuro Kobayashi, Catherin Niemann, Takashi Nomura, Attila Oláh, Mauro Picardo, Sven R Quist, Hironobu Sasano, Marlon R Schneider, Daniel Törőcsik, Sunny Y Wong

Abstract

This review presents several aspects of the innovative concept of sebaceous immunobiology, which summarizes the numerous activities of the sebaceous gland including its classical physiological and pathophysiological tasks, namely sebum production and the development of seborrhea and acne. Sebaceous lipids, which represent 90% of the skin surface lipids in adolescents and adults, are markedly involved in the skin barrier function and perifollicular and dermal innate immune processes, leading to inflammatory skin diseases. Innovative experimental techniques using stem cell and sebocyte models have clarified the roles of distinct stem cells in sebaceous gland physiology and sebocyte function control mechanisms. The sebaceous gland represents an integral part of the pilosebaceous unit and its status is connected to hair follicle morphogenesis. Interestingly, professional inflammatory cells contribute to sebocyte differentiation and homeostasis, whereas the regulation of sebaceous gland function by immune cells is antigen-independent. Inflammation is involved in the very earliest differentiation changes of the pilosebaceous unit in acne. Sebocytes behave as potent immune regulators, integrating into the innate immune responses of the skin. Expressing inflammatory mediators, sebocytes also contribute to the polarization of cutaneous T cells towards the Th17 phenotype. In addition, the immune response of the perifollicular infiltrate depends on factors produced by the sebaceous glands, mostly sebaceous lipids. Human sebocytes in vitro express functional pattern recognition receptors, which are likely to interact with bacteria in acne pathogenesis. Sex steroids, peroxisome proliferator-activated receptor ligands, neuropeptides, endocannabinoids and a selective apoptotic process contribute to a complex regulation of sebocyte-induced immunological reaction in numerous acquired and congenital skin diseases, including hair diseases and atopic dermatitis.

Keywords: developmental biology; hair follicle; immunology; inflammation; sebaceous gland; sebaceous gland disease; sebocyte; stem cells.

Conflict of interest statement

CZ reports thematically relevant, but current work independent, consultancy/advisory boards honoraria from AccureAcne, Almirall, Galderma, General Topics, GSK/Stiefel, L´ORÉAL, Luvos, NAOS-BIODERMA, Pierre Fabre and PPM; he is chair of the ARHS Task Force group of the EADV and Editor of the EADV News. AO provides consultancy services to Monasterium Laboratory Skin & Hair Research Solutions GmbH. MP received a research grant from PPM and provided consultancy to Incyte and Pfizer. The remaining authors declare that the current work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Zouboulis, Coenye, He, Kabashima, Kobayashi, Niemann, Nomura, Oláh, Picardo, Quist, Sasano, Schneider, Törőcsik and Wong.

Figures

Figure 1
Figure 1
Schematic overview of the hair follicle stem and progenitor cell compartments (blue) (A) and distinct cell compartments comprising the mature sebaceous gland (B) including relevant marker molecules expressed by the distinct cell compartments of the mouse telogen hair follicle and the sebaceous duct.
Figure 2
Figure 2
The concept of “sebaceous immunobiology”. Sebum production and composition is regulated by intrinsic (i.e. activators of PPAR and RXR nuclear receptors such as prostaglandins, linoleic acid and endocannabinoids) and extrinsic (i.e. androgens, IGF1, insulin, leptin and retinoic acid) factors. Although the primary role of the lipid rich sebum is to lubricate the hair and to contribute to the lipid barrier of the skin, the composing lipids may penetrate also into the dermis (marked with red arrows). Therefore, they may modulate the functions of keratinocytes, immune cells and presumably of stromal cells by altering their gene and protein expression. Importantly, sebocytes are also able not only to respond to but also to produce a large number of cytokines and chemokines which may be important in maintaining the physiological dermal immune milieu such as the Th17 signature of the sebaceous gland rich skin or hair growth. Regarding its interactions with the microbiota, sebum lipids exert antimicrobial effects, may modulate the macrophage – P. acnes interaction, but are also converted by various microbes into lipids with inflammatory properties, which could have a role not just in the pathogenesis of acne but also in other diseases. These altogether support that a change in the amount and composition of the sebum could modulate (patho)physiological settings and thus may be therapeutic target as well. DCs, dendritic cells; FFA, free fatty acids; IDF1, insulin-like growth factor 1; PPAR, peroxisome proliferator-activated receptors; RAR, retinoic acid receptors; RXR, retinoid X receptors; SG, sebaceous gland; TSLP, thymic stromal lymphopoietin.
Figure 3
Figure 3
Steroidogenic pathways relevant to human sebaceous gland (StAR, steroidogenic acute regulatory protein; P450sc, P450 side chain cleavage; 3β-HSD, 3β-hydroxysteroid dehydrogenase; P450c17, cytochrome P450c17; 17β-HSD, 17β-hydroxysteroid dehydrogenase).
Figure 4
Figure 4
Representative illustration of 3β-hydroxysteroid dehydrogenase (3β-HSD) 1, 3β-HSD2, cytochrome P45011A1 (CYP11A1) and steroidogenic acute regulatory protein (StAR) in human sebaceous gland and its disorders. Marked cytoplasmic 3β-HSD1, CYP11A1 and StAR immunoreactivity was abundant in normal sebaceous glands and weak in pathological sebaceous glands (magnification 200x).
Figure 5
Figure 5
Representative illustration of 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5), 5α-reductase (5α-red)1, 5α-red2 and cytochrome P45017A1 (CYP17A1) immunoreactivity in human sebaceous gland and its disorders.17β-HSD5, 5α-red1 and CYP17A1 immunoreactivity was predominantly detected in normal sebaceous glands compared to pathological sebaceous glands (magnification 200x).
Figure 6
Figure 6
Interaction of sebaceous gland-expressed neuropeptides and sexual hormones. Corticotropin-releasing hormone (CRH) – after binding the corticotropin-releasing hormone receptor 1 (CRHR1) -stimulates sebaceous lipogenesis and testosterone release, while testosterone inhibits the expression of CRHR1. Green symbols and arrows indicate anti-inflammatory activity; red symbols and arrows indicate inflammatory potential. Double lines on the arrows indicate inhibition. Blue symbols indicate targets of the pathway, whereas testosterone might induce a negative feedback to CRH by inhibiting the expression levels of its receptor CRHR1. ø, CRH does probably not inhibit IL1. 3βHSD1, 3β-hydroxysteroid dehydrogensase 1; αMSH, α-melanocortin-stimulating hormone; IL1RA, Interleukin 1 receptor antagonist; NGF, neural growth factor.
Figure 7
Figure 7
Overview of the (endo)cannabinoid system and its putative connections to other signaling systems. The figure was adapted and modified from (190) originally licensed under CC-BY, version 4.0. 5-HT, 5-hydroxytryptamine (serotonin) receptor; A2A and A3, adenosine 2A and 3 receptors; ABDH6 and -12, α/β-hydrolase domain containing 6 and 12; CBC, (-)-cannabichromene; CBD, (-)-cannabidiol; CBDV, (-)-cannabidivarin; CBG, (-)-cannabigerol; CBGV, (-)-cannabigerovarin; CBN, (-)-cannabinol; (-)-cis-PET (–),-cis-perrottetinene; COX2, cyclooxygenase-2; DAGL, diacylglycerol lipase; eCB, endocannabinoid; FAAH, fatty acid amide hydrolase; GPR, G protein-coupled receptor; LOX, lipoxygenase; MAGL, monoacylglycerol lipase; NAAA, N-acylethanolamine hydrolyzing acid amidase; NAPE-PLD, N-acyl phosphatidylethanolamine-specific phospholipase D; PPAR, peroxisome proliferator-activated receptor; PTPN22, protein tyrosine phosphatase non-receptor type 22; THC, (-)-trans-Δ9-tetrahydrocannabinol; THCV, (-)-Δ9-tetrahydrocannabivarin; TRP, transient receptor potential ion channel.
Figure 8
Figure 8
Overview of the effects of the complex cannabinoid signaling on human sebocytes. Sebocytes are able to metabolize endocannabinoids, and express multiple cannabinoid responsive receptors that contribute to the regulation of several aspects of the biology of human sebaceous glands. Importantly, via releasing various cytokines/chemokines as well as controlling the local anti-inflammatory endocannabinoid tone, sebocytes may be capable of shaping cutaneous immune responses. Note that besides CBD, THCV, CBC, and CBDV could also suppress excessive sebaceous lipogenesis, whereas CBG and CBGV induced a moderate increase in the lipid synthesis, and all tested phytocannabinoids were shown to exert anti-inflammatory effects. 2-AG, 2-arachidonoylglycerol; A2A, adenosine 2A receptor; AEA, anandamide; CBC, (-)-cannabichromene; CBD, (-)-cannabidiol; CBDV, (-)-cannabidivarin; CBG, (-)-cannabigerol; CBGV, (-)-cannabigerovarin; DAGL, diacylglycerol lipase; eCB, endocannabinoid; EMT, endocannabinoid membrane transporter; FAAH, fatty acid amide hydrolase; GPR, G protein-coupled receptor; IL, interleukin; MAGL, monoacylglycerol lipase; NAPE-PLD, N-acyl phosphatidylethanolamine-specific phospholipase D; OEA, oleoylethanolamide; PPAR, peroxisome proliferator-activated receptor; THCV, (-)-Δ9-tetrahydrocannabivarin; TLR, toll-like receptor; TNF, tumor necrosis factor; TRPV, transient receptor potential ion channels, vanilloid subfamily; VDM11, a pharmacological inhibitor of EMT.
Figure 9
Figure 9
Eosinophilic pustular folliculitis: An unexpected paradigm of sebaceous gland-controlled immunological reaction. Infection with human polyoma virus or Malassezia as well as the immune reconstitution inflammatory syndrome stimulate the arachidonic acid inflammatory pathway in the sebaceous gland. Prostglandins, downstreem arachidonic acid metabolites, attract eosinophils and basophils to the perisebaceous gland dermis. Indomethacin might exhibit its therapeutic effect by inhibiting cyclooxygenase levels or blocking the chemoattractant receptor homologous molecule expressed on Th2 cells and the chemokine receptor 3. HPyV, human polyoma virus; IRIS, immune reconstitution inflammatory syndrome; AA, arachidonic acid; COX, cyclo-oxygenase; PG, prostaglandin; PGDS, PGD synthase; PPARγ, peroxisome proliferator-activated receptor γ; CRTH2, chemoattractant receptor homologous molecule expressed on Th2 cells; CCR3, C-C motif chemokine receptor 3; CCL26, C-C motif chemokine ligand 26; Eos, eosinophil; Bas, basophil; ILC, innate lymphoid cell.

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Source: PubMed

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