The potential immunomodulatory effects of topical retinoids

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The potential immunomodulatory effects of topical retinoids
David A Jones MD PhD
Dermatology Online Journal 11 (1): 3
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. dajones@partners.org


Abstract

New research has refined our understanding of the immunopathophysiology of acne. Various immune factors, including both innate and adaptive immune responses, have been implicated in the pathophysiology of inflammatory acne. Topical retinoids such as tretinoin, adapalene, and tazarotene, exhibit immunomodulatory effects that may help to explain their efficacy in the resolution of inflammatory lesions.

The immunopathophysiology of acne revised

An immune basis for the pathophysiology of acne vulgaris has long been recognized. Inflammation is well established as one of the four pathophysiologic factors in the development of acne vulgaris. In the 1970s Kligman suggested that the initial inflammatory event in acne vulgaris involved the disruption of the follicular epithelium into the dermis, allowing the comedonal contents to have contact with the vascular and immune systems [1]. Kligman and others believed that neutrophils were the first immune cells involved in the follicular inflammation, and for many years neutrophils along with the pathogen Propionibacterium acnes (P. acnes) were regarded as the fundamental instigators of the inflammation in acne [1, 2, 3] More recent research refines our understanding of the pathophysiology of acne vulgaris and suggests a more complex pathophysiology than previously suspected. This review will discuss a portion of this acne research focusing on direct immunomodulatory properties of retinoids.

Follicular wall permeability versus overt rupture

The inflammatory process which results in acne lesions is complex, involving interactions among multiple cell types and many soluble mediators. Structural abnormalities of the follicle including comedone formation are also important in the development of inflammatory acne, but overt rupture of comedones may not be a required initiating event. Eady and Cove have suggested that increased permeability of the follicular wall secondary to the release of the proinflammatory and cell-differentiating cytokine interleukin 1 alpha (IL-1α) may be all that is necessary to initiate the intradermal inflammatory process that characterizes inflammatory lesions [4].

Neutrophils versus T-cell lymphocytes as the primary instigators of the immunopathophysiology of acne

As noted, Kligman and subsequent researchers suggest that neutrophils are the first immune cells in acne lesions [1, 2]. However, Cunliffe and Norris challenge this view; their biopsies demonstrate T lymphocytes to be the predominant cells in early inflammatory lesions [5]. More research will be required to reproduce and refine these observations. Subsequent in vitro studies have demonstrated that antigens from P. acnes can stimulate the development of subclasses of T cells [6]. Whether neutrophils or lymphocytes are first at the lesion site, evidence suggests that both immune cells are involved in the immunopathophysiology of acne.

The role of P. acnes as an instigator of inflammation

Zouboulis has questioned the predominant role of P. acnes as an instigator of inflammation in acne lesions. He suggests that the pilosebaceous gland itself may be the origin of certain immune factors, although the presence of a pathogen such as P. acnes may amplify this initial immune response [7]. In vitro studies demonstrate that IL-1α can be synthesized by sebocytes and follicular keratinocytes without the presence of microorganisms [8, 9]. It is also suggested that the free fatty acids in sebum and certain leukotrienes, which are proinflammatory mediators derived from arachidonic acid, are also involved in the immunopathophysiology of acne [7].

The identification of novel immune factors: human β defensins and toll-like receptors

Recent progress in the study of innate immunity identifies two key factors relevant to acne: β defensins and toll-like receptors (TLRs). This identification brings the elucidation of the immunopathophysiology full circle by again implicating microflora such as P. acnes in the etiology of acne vulgaris. Human β defensins are antimicrobial peptides [10]. The role of these peptides in various plant and animal species is to protect against various pathogens, such as bacteria [10]. A recent in vitro study examines biopsies of normal pilosebaceous follicles from the backs of healthy patients and those with inflammatory lesions. Human β defensin-1 and -2 are found to be upregulated in inflammatory acne lesions. The researchers suggest that this upregulation of β defensins may be a protective mechanism for controlling pathogens in patients with acne [10].

Toll-like receptors (TLRs) are expressed on human macrophages and identify general molecular patterns that occur on bacteria and other pathogens but not on the host [11]. As such, they are a key subset of pattern recognition receptors (PRRs) [11]. This receptor recognition is critical to the innate immune response.

Figure 1
Actions of toll-like receptors on antigen-presenting cell (dendritic cell) in activating subsets of T cells.

It now appears that this interaction between the pathogen-associated molecular pattern (PAMP) and the TLR is also critical to the adaptive immune response [11]. Specifically, this interaction is now thought to be necessary before a macrophage can release IL-1α. This cytokine in turn activates the macrophage through an autocrine process and also activates subsets of helper T cells (Fig. 1) [11].

It is known that P. acnes can induce monocytes to secrete proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin-8 (IL-8) [12]. TLRs appear to be involved in mediating the activation of monocytes, ultimately resulting in the release of these proinflammatory cytokines. When these receptor subtypes are activated by cell-wall components of gram-positive bacteria, such as P. acnes, or by lipopolysaccharides of gram-negative bacteria, they begin intracellular signaling of transcription factors for various proinflammatory mediators [13]. A recent study of macrophages from mice with TLR-1 and TLR-6 receptors removed, but TLR-2 receptors intact, demonstrates that P. acnes induces the release of IL-12 and IL-8. A monoclonal antibody to the TLR-2 receptor inhibits the release of these proinflammatory cytokines. The researchers conclude that P. acnes induces the release of proinflammatory cytokines by activation of the TLR-2 receptor [14].

The potential immunomodulating effects of topical retinoids

Topical retinoids (e.g., tretinoin, adapalene, and tazarotene) normalize hyperkeratinization and thereby exert indirect immunomodulatory effects by changing the comedonal environment [15]. In essence, by preventing hypercornification of the pilosebaceous unit, they promote a more aerobic environment inhospitable to P. acnes [16]. However, in vitro and in vivo studies suggest that topical retinoids also demonstrate direct effects on a number of additional immune factors implicated in the pathophysiology of acne vulgaris.

In vitro models

A number of in vitro models were used to study the anti-inflammatory effects of retinoids (tretinoin, adapalene, isotretinoin, and etretinate); a corticosteroid (betamethasone-17-valerate); and a nonsteroidal anti-inflammatory drug (NSAID, indomethacin) [17]. The actions of these agents on a number of inflammatory mediators and mechanisms were assessed. These included the activity of 15-lipoxygenase, the enzyme responsible for the conversion of arachidonic acid to a leukotriene family of inflammatory mediators; the production of other eicosanoids (5- and 15-hydroxyeicosatetraenoic acid or HETE); and chemotaxis. Adapalene is associated with greater inhibition of the lipoxygenase pathways and greater inhibition of leukotriene production compared with all other agents, including the other retinoids tested. Adapalene and tretinoin also demonstrate significant inhibition of oxygen free radicals released from PMNs derived from rabbits. Adapalene also inhibits human chemotaxis of PMNs (Table 1) [17, 18].

Figure 2
Effect of adapalene and tretinoin (retinoic acid) on down-regulating TLR2 expression on monocytes.

A recent in vitro study involving the retinoids adapalene and tretinoin, demonstrates that these agents inhibit the expression of mammalian TLR-2 on human monocytes derived from healthy volunteers [13]. First, monoclonal antibodies were used to determine the expression of TLR receptors. After 4 days of culture, TLR-2 is strongly expressed in untreated cells, whereas TLR-4 is only weakly expressed. The monocytes then were cultured with different concentrations of the two retinoids. At low concentrations of retinoids, approximately 100 percent of the monocytes express TLR-2 (Fig. 2). At higher concentrations, only approximately 20 percent of monocytes express this receptor [13]. It is interesting to note that the retinoid concentration achieved in follicles is actually higher than the concentrations used in this in vitro study.

In vivo animal models

Ultraviolet (UV) light irradiation is used to induce erythema in animal models. In a guinea pig model, both adapalene and tretinoin significantly decreased erythema [17].

Cutaneous inflammation can be induced through use of croton oil. This type of skin inflammation can be inhibited by corticosteroids but not by NSAIDs. In this animal model, adapalene demonstrates moderate inhibition of inflammation; tretinoin exhibits very little effect. Although both retinoids exhibit anti-inflammatory effects, the findings of this study suggest that adapalene and tretinoin may address different aspects of inflammation (Table 2) [17, 18].

The prostaglandin and leukotriene family of inflammatory mediators are both derived from arachidonic acid. In the arachidonic acid-induced ear edema mouse model, adapalene is associated with significant anti-inflammatory effects; tretinoin is associated with less inhibition (Table 2) [17, 18].

Another animal model of inflammation involves edema induced by carrageenan. NSAIDs exert significant anti-inflammatory effects in this model [17]. In a rat model, adapalene demonstrates anti-inflammatory effects equivalent to those of indomethacin; tretinoin does not demonstrate significant anti-inflammatory effects (Table 2) [17].

The therapeutic implications of retinoid immunomodulatory effects

On the basis of their immunomodulatory actions, topical retinoids are expected to effectively reduce inflammatory lesions, in addition to comedones. The degree to which each particular mechanism functions in human acne remains to be tested to validate the in vitro and animal studies reviewed above. However, the reduction in inflammation demonstrated in preclinical studies have been validated by clinical trials. Various formulations of adapalene (gel, cream, solution), tretinoin (gel, microsphere gel, cream), and tazarotene gel are all found to significantly reduce inflammatory lesions in well-controlled clinical trials [19, 20, 21, 22, 23, 24, 25, 26]. Indeed, topical retinoids are recommended as therapy for all stages of acne except the most severe inflammatory stage [27].

Of course, criteria for choice of acne therapy involve not just efficacy in the treatment of noninflammatory and inflammatory lesions but tolerability and the potential for medication compliance. All topical retinoids can be associated with cutaneous irritation that can interfere with compliance. Adapalene is found to have the best cutaneous tolerability [19, 20, 22, 23, 26]. Other therapeutic strategies to decrease the potential for cutaneous irritation involves the use of new delivery systems such as the tretinoin microsponge system, and alternative dosing regimens (e.g., QOD or short-contact therapy) that are used to subdue the cutaneous irritation seen with tazarotene [28, 29, 30].

Conclusion

An increasing understanding of the complexity of the pathophysiology of acne vulgaris is guiding practitioners in their choice of therapeutic agents. The immunomodulatory effects of topical retinoids provide a rationale for using these agents in the treatment not only of comedones but also of inflammatory lesions as well.
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