Innate immunity in the pathogenesis of acne vulgaris

INTRODUCTION

Acne vulgaris is a disease of pilosebaceous units. Major hypotheses on its pathophysiology include the following (1,2):

  1. Altered follicular keratinization (hyperkeratinization) of the pilosebaceous unit (3)
  2. Propionibacterium acnes (P. acnes) follicular colonization and activity (4)
  3. Hormonal influence (5 7)
  4. Sebum production (8)
  5. Release of inflammatory mediators (4,9)

These hypotheses have traditionally been viewed as independent factors that, as a whole, contribute to acne pathogenesis.

In particular, inflammation has been viewed as a distinct contributor to acne, but the mechanism by which this occurred was not well elucidated. Recent advances in molecular and cellular studies now reveal that inflammation promotes acne via activation of the innate immune system. In addition, studies now show that mechanisms involving the innate immune system could initiate and influence many of the traditionally described factors in acne pathogenesis, as listed above (1,10 12). The importance of the innate immune system in the pathogenesis of acne is a significant advance in our understanding of acne with important implications for treatment. Therefore, this post focuses on new and evolving insights into the role of the innate immune system in association with acne, specifically on the manner in which these new findings build upon traditionally known pathogenetic factors and suggest additional hypotheses of acne pathophysiology. These new hypo-theses include the following:

  1. Inflammatory events mediated by interleukin 1 (IL-1) precede hyper-keratinization (9,13 15).
  2. P. acnes activates the innate immune system via Toll-like receptors (TLRs) (16,17).
  3. P. acnes induces matrix metalloproteinase (MMP) (18,19) and antimicrobial peptide (AMP) production (20 22).
  4. Sebaceous gland lipids influence the innate immune system (23,24).

CUTANEOUS IMMUNE SYSTEM

The human immune system is comprised of two distinct functional parts: innate and adaptive (25). These two components have different types of recognition receptors and differ in the speed in which they respond to a potential threat to the host. While the innate immune system responds rapidly to commonly shared pathogen structures and lacks memory, the adaptive immune response is delayed to specific antigens and retains memory against the pathogen (25). The specific components of the cutaneous innate immune system include barriers such as the skin and mucosal epithelium (25); soluble factors such as complement, antimicrobial peptides, chemokines, and cytokines (26); cells including keratinocytes, monocytes/macrophages, dendritic cells (DCs), natural killer cells (NK cells) and polymorphonuclear cells (PMNs), or neutrophils. Cells use pattern recognition receptors (PRRs) encoded directly by the germline DNA to respond to specific pathogen-associated molecular patterns (PAMPs) shared by a variety of different pathogens to elicit a rapid response against these pathogens (25).

The skin provides important functions in innate immunity. As the largest organ in the human body, the skin provides a vital and direct barrier from exogenous toxins. The stratum corneum is composed of highly cross-linked proteinaceous cellular envelopes with extracellular lipid lamellae consisting of ceramides, free fatty acids, and cholesterol (27). The free fatty acids create an acidic environment that inhibits colonization by certain bacteria such as Staphylococcus aureus, providing further protection (27). Soluble factors such as complement, antimicrobial peptides, chemokines, and cytokines provide an additional critical layer of innate immune defense for those pathogens that overcome the physical barrier (25,26).

Importantly, the cutaneous innate immune system also provides rapid cellular responses enacted by keratinocytes, melanocytes, and Langerhans cells, and by recruitment of DCs, monocytes/macrophages, NK cells, and PMNs to protect a newly infected host (25). These cells express PRRs that mediate responses to PAMPs that are conserved among microorganisms. While there are many families of PRRs, human TLRs are one such family that is capable of initiating innate immune responses and influencing subsequent adaptive immune responses (25).

TLRs were first identified in Drosophila, and mammalian homologs have been shown to mediate immune responses to microbial ligands (25,28,29). TLRs are transmembrane proteins capable of mediating responses to PAMPs conserved among microorganisms. The extracellular portion of TLRs is composed of leucine-rich repeats while the intracellular portion shares homology with the cytoplasmic domain of the IL-1 receptor (25,28,29). When TLRs are activated by exposure to microbial ligands, the intracellular domain of certain TLRs trigger a MyD88-dependent pathway, while other pathways are MyD88 inde-pendent. This leads to the nuclear translocation of the transcription factor nuclear factor xB (NF-xB), which acts to modulate expression of many immune response genes. The activation of these TLRs and their downstream pathways ultimately leads to the release of critical proinflammatory and immunomodulatory cytokines such as IL-1, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor-alpha (TNF-oc) (25,28,29).

Currently, 11 TLR genes have been identified in humans (25,29). The microbial ligands for many of these receptors have been demonstrated and include bacterial cell wall components and genetic material. More specifically, TLR2 mediates responses to peptidoglycan from gram-positive bacteria (30 32); TLR4 mediates host responses to bacterial lipopolysaccharide from gram-negative bacteria (30 32); and TLR5 mediates the host response to bacterial flagellin (33). In addition, TLR9 mediates the response to the unmethylated CpG DNA comprising bacterial genomes; and TLR3 mediates responses to viral double-stranded RNA (34,35). Furthermore, TLR heterodimers have been shown to mediate responses to microbial lipoproteins, with TLR2/1 heterodimers mediating responses to triacylated lipoproteins and TLR2/6 heterodimers mediating responses to diacylated lipoproteins (36,37). P. acnes can activate TLR2, but the exact molecular structure of the TLR2 ligand has not been defined (16,17,28).

Taken together, the cutaneous innate immune system comprises a specific immunologic environment in which pathogens that evade the physical and chemical barrier of the skin itself are rapidly detected by pathogen receptors such as TLRs and destroyed by effector cells, such as PMNs or NKs, and secreted soluble substances, such as antimicrobial peptides. However, this sequence of events, while acting against a pathogen, can also trigger inflammatory responses that result in tissue injury, alterations in tissue growth cycles, and local changes in the tissue environment that lead to disease states (17). Evidence now suggests that acne lesions express different levels of innate immune system components than normal skin (10) and that upregulation and activation of these components and their downstream pathways in the cutaneous innate immune system result in the clinical manifestations of acne (1,11,17,28,38,39). Multiple components of the innate immune system contribute to acne pathogenesis, including derangements in barrier function of the skin itself, upregulation of soluble factors such as chemokines, cytokines, and antimicrobial peptides, and alteration of downstream effector pathways activated by pathogen recognition of P. acnes. These events precede and promote acne formation and contribute to our current understanding of acne pathogenesis.

INFLAMMATORY EVENTS PRECEDE HYPERKERATINIZATION

Acne develops in the pilosebaceous unit. While the exact sequence and nature of the events that initiate and promote acne are not fully understood, it is generally believed that one of the early events is the obstruction of the pilosebaceous follicles (17). This occurs when the follicular infundibulum becomes occluded by either hyperkeratinization or hyperproliferation of keratinocytes or both. This results in the formation of the microcomedone, which is the earliest subclinical acne lesion, characterized by hyperproliferation of the follicular epithelium (17). Recent evidence suggests that inflammatory events not only precede hyper-keratinization but also initiate and promote hyperkeratinization.

Jeremy et al. demonstrated that early inflamed acne lesions exhibited increased expression of the cytokine IL-1 (14). Their work suggests that upregulation of IL-1 could be initiated by perturbation of the barrier function within an individual follicle due to increased sebum production and a relative deficiency of linoleic acid, which normally acts to preserve the integrity of the follicle (13,40,41). This breakdown of barrier function then triggers the innate immune response resulting in the release of IL-1, a potent proinflammatory cytokine, which stimulates an inflammatory cascade including the activation of local endothelial cells and upregulation of inflammatory vascular markers such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and human leukocyte antigen DR (HLA-DR) in the vasculature around the pilosebaceous follicle (14). The authors suggest that these immune changes and inflammatory responses occur before hyper-proliferation of keratinocytes in a manner similar to a type IV delayed hyper-sensitivity response (14).

The importance of IL-1 production as a critical initiating event of follicular hyperkeratinization coincides with the concept of the “keratinocyte activation cycle” (42,43). It is proposed that in a number of pathologic conditions, keratin-ocytes can either undergo activation or differentiation. While differentiation allows the keratinocyte to slowly proliferate in the basal layer and differentiate in the suprabasal layers, activation promotes hyperproliferation, migration, cytoskeletal change, and increased production of signaling molecules (42,43). IL-1 production is initiated by injured keratinocytes and activates paracrine signaling, attracting lymphocytes, stimulating selectins, and signaling migration of fibroblasts. IL-1 also acts in an autocrine fashion, activating keratinocytes to migrate, proliferate, and produce IL-1, granulocyte-macrophage colony stimulating factor (GM-CSF), TNF-oc, ICAM-1, and integrins. Together, these further activate and sustain hyper-keratinization (14,42,43).

Thus, it is believed that inflammatory events, specifically the production of IL-1, precede and contribute to hyperkeratinization. While the exact initial event is not known, one hypothesis is that increased sebum production with a relative deficiency of specific fatty acids disrupts the normal lipid layers that protect the skin and allow the skin to act as a barrier to pathogens (14,15). This imbalance, along with physical injury, leads to IL-1 release from keratinocytes resulting in sustained activation of the keratinocyte, which triggers hyperkeratinization and hyperproliferation. Although the full sequence of events that initiate acne are not understood, the role of IL-1 as an early component of hyperkeratinization is an important new concept in our understanding of the innate immune response in the pathogenesis of acne lesions. Furthermore, this evidence that inflammation is the basis of an early acne lesion suggests that therapy should be directed at reducing inflammation, both for treating new acne lesions as well as for maintenance.

PROPIONIBACTERIUM ACNES PROMOTES INFLAMMATION VIA TLRS

P. acnes is an anaerobic gram-positive, rod-shaped bacterium. It is a commensal organism that resides on most human skin (including non-acne-prone skin) and survives on fatty acids found in the sebum produced by sebaceous glands. It is unique in that its cell wall and outer envelope produce phosphatidyl inositol, which typically is produced only in eukaryotes. In addition, the peptidoglycan of the cell wall of P. acnes contains a cross-linkage region of peptide chains with L, L-diaminopimelic acid and D-alanine in which two glycine residues combine with amino and carboxyl groups. These features are notable as they may contribute to the recognition of P. acnes as a pathogen by human immune cells. In response to P. acnes, innate immune cells produce proinflammatory cytokines, including TNF-oc and IL-10 (44). The chemotactic factor IL-8 is also induced by P. acnes (45,46). These soluble molecules play an important role in attracting neutrophils and monocytes/macrophages to the pilosebaceous follicles in acne lesions, which are then activated to further produce other inflammatory mediators.

The importance of P. acnes as an etiological factor of acne has long been known, and early studies demonstrated greater numbers of P. acnes in affected skin versus matched controls (47). Studies also showed that its injection into the skin promoted vigorous inflammatory responses (48). In a seminal paper, Vowels et al. found that the presence of a soluble factor of P. acnes induced proinflammatory cytokine production in monocytes, including TNF-oc and IL-1R. Moreover, activation of inflammation was dependent on CD14, a known PRR for lipid-containing ligands, such as lipopolysaccharide (4).

Although the role of P. acnes as an etiological factor in inflammation associated with acne had been established, the exact mechanism of its action was described only recently. It is now known that P. acnes is recognized by TLRs and activates the innate immune system. Kim et al. demonstrated that transfection of TLR2 into a nonresponsive cell line was sufficient for NF-xB activation in response to P. acnes (16,17). Further, they demonstrated that P. acnes induces IL-12 and IL-8 production by human monocytes via activation of TLR2. They also demonstrated that TLR2 expression was found in macrophages in biopsied acne lesions, particularly in the perifollicular regions, and the quantity of TLR2- positive cells detected increased with the increasing age of the lesion. Following these findings, Jugeau et al. demonstrated that TLR2 and TLR4 expression are upregulated in acne lesions of patients with facial acne and that TLR2 and TLR4 expression increased within hours of incubating human keratinocytes with bacterial fractions (49). Although the exact P. acnes TLR2ligand is unknown, it is postulated that P. acnes peptidoglycan on the cell wall serves as the PAMP for TLR2. Taken together, it seems that P. acnes contributes to the pathogenesis of acne by inducing inflammation through the activation of TLR2 and the subse-quent release of cytokines, which regulate the local immune response.

PROPIONIBACTERIUM ACNES INDUCES MMP PRODUCTION

In addition to cytokines and chemokines, MMPs are also mediators of immunity and inflammation, tissue destruction, and scar formation. MMPs play a role in several inflammatory conditions, including rheumatoid arthritis and arterial inflammation, and possibly also in infectious diseases such as Lyme disease and tuberculosis. MMP-1, MMP-3, and MMP-9 have been found in acne lesions (10), and recent studies have shown that MMPs can participate in the innate immune response and induce inflammation. Jalian et al. showed that P. acnes upregulates MMP-1 and MMP-9 (18), and Choi et al. showed that P. acnes upregulates MMP-2 (19). The activation of MMP-1 and MMP-9 appears to occur through the transcription factor activator protein-1 (AP-1) (50), and recently the activation of MMP-1, MMP-9, and AP-1 has been shown to be found in acne lesions (51). Interestingly, Jalian et al. also demonstrated that all-trans retinoic acid (ATRA) inhibited P. acnes induced upregulation of MMPs while downregulating tissue inhibitor of metalloproteinase (TIMP), suggesting that ATRA shifts a tissue-degrading phenotype to a tissue-pre-serving phenotype (18). This may explain the clinical findings that ATRA and other retinoids improve acne scarring. Furthermore, such studies suggest that ATRA may be useful for adjuvant therapy to prevent and treat acne scar formation.

PROPIONIBACTERIUM ACNES INDUCES ANTIMICROBIAL PEPTIDE PRODUCTION AND ANTIMICROBIAL RESPONSE

The innate immune system must rapidly recognize microbial pathogens and trigger direct host antimicrobial response to limit the infection, yet the activation of the innate immune system also results in inflammation and tissue injury that characterize the clinical manifestations of human disease. This “double-edged sword” of innate immunity is clearly evident in acne vulgaris in which innate immune cells mount an antimicrobial response to P. acnes, but they also induce an inflammatory response mediated by release of cytokines, chemokines, and MMPs that contribute to clinical disease. The previous sections focused on the production of cytokines, chemokines, and MMPs. Here we discuss briefly the antimicrobial response in acne.

Antimicrobial peptides produced in the skin play a critical role in the elimination of the invading microorganisms. Important antimicrobial peptides in skin include human R-defensins 1 and 2 (HBD1 and HBD2). HBD2 is an important host defense molecule due to its ability to kill microorganisms and to recruit and activate macrophages and DCs (22). Antimicrobial peptide HBD2 is induced by proinflammatory cytokines such as IL-10 and TNFoc and bacterial components (21). Chronnell et al. found that HBD2 expression is upregulated in acne lesions (22). Additionally, it has been shown that two different strains of P. acnes can induce HBD-2 in cultured keratinocytes and that P. acnes induces elevation of HBD2 and IL-8 via TLR2- and TLR4-mediated mechanisms (20). Furthermore, HBD2 has shown to have direct antimicrobial activity against P. acnes in synergy with cathelicidin (52).

Cathelicidin (LL-37) is another important antimicrobial peptide that is upregulated by P. acnes extracts in sebocytes, keratinocytes, and monocytes (53). It has also been demonstrated that cathelicidin and granulysin, another antimicrobial peptide, can kill P. acnes (52,53). Moreover, cathelicidin, HBD2, and psoriasin (another antimicrobial peptide found in acne lesions) provide synergistic action against P. acnes and other gram-positive organisms and recruit inflammatory mediators (20,21,53,54). Therefore, it is likely that antimicrobial peptides contribute to control local bacterial growth, but at the same time induce inflammatory responses in acne.

P. acnes has also been shown to directly induce the differentiation of cells involved in the phagocytosis of microbes, specifically the differentiation of monocytes to specific macrophages that express CD209. These CD209 macro-phages are efficient phagocytic cells able to induce intracellular killing of pathogens. A study by Liu et al. demonstrated that CD209+ macrophages are able to phagocytose P. acnes and kill them intracellularly (56). While the mechanism of this killing was not demonstrated, the authors suggest that anti-microbial peptides such as HBD2 or LL-37 may play a role. Interestingly, the authors also demonstrated that ATRA alone induces the differentiation of human monocytes into CD209+ macrophages, suggesting an indirect antimicrobial property of ATRA. Studies in this and previous sections show that P. acnes activate two differential host innate immune responses induction of inflam-mation that contributes to disease pathogenesis and induction of antimicrobial response by the host that contributes to control the growth of P. acnes. Future therapy should target and balance these two distinct innate immune responses found in acne.

INNATE IMMUNITY IN THE PATHOGENESIS OF ACNE VULGARIS SEBACEOUS GLAND LIPIDS INFLUENCE IMMUNE RESPONSES

Previously, the sebaceous glands were presumed to provide only a lubricating function for the skin and hair with its sole function of producing lipids. However, recent findings have shown that sebocytes as innate immune cells are capable of pattern recognition and mounting an immune response. A study by Nagy et al. demonstrated that P. acnes induce the expression of HBD2 and proinflammatory cytokines TNF-oc and IL-1a and chemokine CXCL8 in a human sebocyte cell line (20,21). Nelson et al. have also shown that 13-cis retinoic acid can induce apoptosis of human sebocytes via a neutrophil gelatinase-associated lipocalin (NGAL) dependent mechanism, which may help to explain how this therapeutic works to treat severe acne (57). Therefore, similar to other innate immune cells, sebocytes recognize pathogens and are capable of inducing both inflammation and antimicrobial responses. Understanding the biology of sebocytes in the setting of both inflammation and antimicrobial responses may provide clues to the development of other therapeutics for acne.

Sebum production by the sebaceous gland is a well-established cause of acne. Sebum is a lipid-rich fluid that is a nutrient source for P. acnes and consists of cholesterol, fatty acids, fatty alcohols, di- and triglycerides, wax esters, sterol esters, and squalene (58). While other mammals have sebaceous glands, human sebum is specific and uniquely contains wax esters and squalene. Furthermore, humans are the only mammals to suffer from acne. The sebaceous gland is capable of synthesizing cholesterol de novo, under the influence of various steroidogenic genes that are regulated in a tissue-specific fashion, and converting this precursor to various cholesterol derivatives (6). Important lipids in acne pathogenesis include squalene (59), arachidonic acid, linoleic acid, palmitic acid, and sapneic acid, as these lipids have been shown to influence inflammation in acne (24).

In addition to antimicrobial peptides, there is also evidence to suggest that lipids could function as antimicrobial agents, for example, sapienic acid was found to be effective against S. aureus (55).

Sebaceous gland lipids have been found to exert direct inflammatory effects. Oxidized squalene can stimulate hyperproliferative behavior of keratinocytes and induce an initial upregulation of IL-6 production lip-oxygenases activity, such as 5-lipoxygenase (5-LOX) (24,60). 5-LOX can sub-sequently metabolize arachidonic acid to leukotriene B4 (LTB4), which induces recruitment and activation of neutrophils, monocytes, and eosinophils. 5-LOX also stimulates the production of several proinflammatory cytokines and medi-ators that augment tissue inflammation. 5-LOX production is enhanced in the sebaceous glands of acne patients (60), and its in vivo inhibition reduces the production of proinflammatory sebaceous fatty acids as well as the number of inflammatory acne lesions (61,62). In addition, it has been shown that arachidonic acid and linoleic acid stimulate IL-6 and IL-8 synthesis and enhance the synthesis of sebaceous lipids (60) and that ceramides, another family of lipid molecules, contribute to neutrophil degranulation and increase integrin expres-sion on leukocytes, which increases leukocyte recruitment to the area of inflammation. These studies suggest that lipids produced in the sebaceous gland, act in a direct, tissue-specific fashion to promote innate immune responses that contribute to acne pathogenesis.

In addition to directly promoting acne, sebum lipids have also been shown to promote downstream inflammatory pathways. These downstream effects include activation of nuclear receptors, which then regulate genes involved in inflammation and the innate immune system. Peroxisome proliferator activated receptors (PPARs) are a class of nuclear receptors that are able to regulate transcription of DNA. It has been suggested that these nuclear receptors are regulated by fatty acid derivatives and can control inflammatory response genes. An example of this is the finding that LTB4, converted by 5-LOX from arach-idonic acid, binds and activates PPARoc, which can inhibit the expression of proinflammatory genes that regulate the production of cytokines, MMPs, and acute-phase proteins (63). In addition, a different prostaglandin (15d-PGJ2) has been reported to be an endogenous activator of PPARy, which augments lipo-genesis (64). Lastly, it has also been suggested that nuclear receptors activated by sebum lipids can activate T-cell signaling pathways and regulate further lipid production through AP-1 and NF-xB signals (65). More research is needed to further understand the downstream effects of sebum lipids on the innate immune system.

Taken together, these results support the view that sebum lipids induce inflammation and activate the innate immune system via direct and downstream effects. Furthermore, sebum lipids exert both pro- and anti-inflammatory effects, and the interplay between these in various skin sites and types could contribute to differences in acne expression.

CONCLUSION

The accepted pathogenic factors of acne have traditionally included complex interactions between sebum production by the sebaceous gland, P. acnes follicular colonization, alteration in the keratinization process, and hormone regulation. In this post, we discussed acne pathogenesis related to innate immunity. The skin is an efficient immune organ that uses the innate immune response to protect the host. On the other hand, the same mechanism that leads to antimicrobial responses can lead to the release of inflammatory mediators contributing to disease. While the precise mechanisms of these interactions are not fully understood, with the advent of cellular culture studies and advanced immunology techniques, it has been increasingly demonstrated that acne is a disease of innate immunity and that previously known pathogenic factors likely interact with various immune mechanisms to promote acne pathogenesis.

While it has classically been thought that alterations in keratinization lead to inflammatory events, it is now believed that inflammatory events through IL-1 precede hyperkeratinization. Similarly, the role of P. acnes has been further elucidated to demonstrate that P. acnes activation of innate immune cells including keratinocytes, monocytes/macrophages, and sebocytes leads to inflammation, including the expression of cytokines, chemokines, and MMPs. In addition, it has been demonstrated that the sebaceous gland participates in the immune response and that sebum lipids exert both direct inflammatory effects and indirect regulation of downstream inflammatory pathways. It is becoming clear that acne is an inflammatory and immune-related disease and future acne therapies should target these pathways.

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Jean-Paul Marat

Many tips are based on recent research, while others were known in ancient times. But they have all been proven to be effective. So keep this website close at hand and make the advice it offers a part of your daily life.